Respiratory syncytial virus replication inhibitors

ABSTRACT

The present invention concerns compounds of formula (I), prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof wherein -a 1 =a 2 -a 3 =a 4 -represents a radical of formula —CH═CH—CH═CH—; —N—CH—CH═CH—; —CH═N—CH═CH—; —CH═CH—N═CH—; —CH═CH—CH═N—; wherein each hydrogen atom may optionally be substituted; Q is a radical of formulae (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7) and (b-8), wherein Alk is C 1-6 alkanediyl; Y 1  is a bivalent radical of formula —NR 2 — or —CH(NR 2 R 4 )—; X 1  is NR 4 , S, S(═O), S(═O) 2 , O, CH 2 , C(═O), CH(═CH 2 ), CH(OH), CH(CH 3 ), CH(OCH 3 ), CH(SCH 3 ), CH(NR 5a R 5b ), CH 2 —NR 4  or NR 4 —CH 2 ; X 2  is a direct bond, CH 2 , C(═O), NR 4 , C 1-4 alkyl-NR 4 , NR 4 —C 1-4 alkyl, t is 2 to 5; u is 1 to 5; v is 2 or 3; and whereby each hydrogen in Alk and in (b-3), (b-4), (b-5), (b-6), (b-7) and (b-8), may optionally be replaced by R 3 : provided that when R 3  is hydroxy or C 1-6 alkyloxy, then R 3  cannot replace a hydrogen atom in the a position relative to a nitrogen atom; G is a direct bond or optionally substituted C 1-10 alkanediyl; R 1  is an optionally substituted bicyclic heterocycle; R 2  is hydrogen, formyl, C 1-6 alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C 3-7 cycloalkyl or C 1-10 alkyl substituted with N(R 6 ) 2  and optionally with another substituent; R 3  is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, aryl C 1-6 alkyl or aryl C 1-6 alkyloxy, R 4  is hydrogen, C 1-6 alkyl or aryl C 1-6 alkyl; R 5a , R 5b , R 5c  and R 5d  are hydrogen or C 1-6 alkyl; or R 5a  and R 5b , or R 5c  and R 5d  taken together from a bivalent radical of formula —(CH 2 ) 5 - wherein S is 4 or 5; R 6  is hydrogen, C 1-4 alkyl, formyl, hydroxy C 1-6 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkyloxycarbonyl; aryl is optionally substituted phenyl; Het is pyridyl, pyrimidinyl, pyridazinyl, pyridazinyl; as respiratory syncytial virus replication inhibitors; their preparation, compositions containing them and their use as a medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is an application filed under 35 U.S.C. § 371 ofPCT/EP00/05677 filed Jun. 20, 2000, which claims priority to EPO99202089.1 filed Jun. 28, 1999, the disclosures of which areincorporated herein by reference in their entirety.

The present invention is concerned with benzimidazoles andimidazopyridines having antiviral activity, in particular, they have aninhibitory activity on the replication of the respiratory syncytialvirus. It further concerns their preparation and compositions comprisingthem, as well as their use as a medicine.

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumovirinae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.Ribavirin, a nucleoside analogue, provides an aerosol treatment forserious RSV infection in hospitalized children. The aerosol route ofadministration, the toxicity (risk of teratogenicity), the cost and thehighly variable efficacy limit its use. The other two drugs, RespiGam®and palivizumab, polyclonal and monoclonal antibody immunostimulants,are intended to be used in a preventive way.

Other attempts to develop a safe and effective RSV vaccine have all metwith failure thus far. Inactivated vaccines failed to protect againstdisease, and in fact in some cases enhanced disease during subsequentinfection. Life attenuated vaccines have been tried with limitedsuccess. Clearly there is a need for an efficacious non-toxic and easyto administer drug against RSV replication.

EP-A-0,005,318, EP-A-0,099,139, EP-A-0,145,037, EP-A-0,144,101,EP-A-0,151,826, EP-A-0,151,824, EP-A-0,232,937, EP-A-0,295,742, EP0,297,661, EP-A-0,307,014, WO 92 01697 describe benzimidazole andimidazopyridine substituted piperidine and piperazine derivatives asantihistaminics, antiallergics or serotonine antagonists.

Thus, the present invention concerns the compounds of formula (I)

their prodrugs, N-oxides, addition salts, quaternary amines, metalcomplexes and stereochemically isomeric forms wherein

-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula

—CH═CH—CH═CH— (a-1); —N═CH—CH═CH— (a-2); —CH═N—CH═CH— (a-3);—CH═CH—N═CH— (a-4); or —CH═CH—CH═N— (a-5);

-   -   wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3),        (a-4) and (a-5) may optionally be replaced by halo, C₁₋₆alkyl,        nitro, amino, hydroxy, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl,        carboxyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,        C₁₋₄alkyloxycarbonyl, hydroxyC₁₋₆alkyl, or a radical of formula

-   -    wherein ═Z is ═O, ═CH_C(═O)_NR^(5a)R^(5b), ═CH₂, ═CH—C₁₋₆alkyl,        ═N—OH or ═N—O—C₁ alkyl;

-   Q is a radical of formula

-   wherein Alk is C₁₋₆alkanediyl;    -   Y¹ is a bivalent radical of formula —NR²_or —CH(NR²R⁴)—;    -   X¹ is NR⁴, S, S(═O), S(═O)₂, O, CH₂, C(═O), C(═CH₂), CH(OH),        CH(CH₃),    -   CH(OCH₃), CH(SCH₃), CH(NR^(5a)R^(5b)), CH₂—NR⁴ or NR⁴—CH₂;    -   X² is a direct bond, CH₂, C(═O), NR⁴, C₁₋₄alkyl-NR⁴,        NR⁴—C₁₋₄alkyl;    -   t is 2, 3, 4 or 5;    -   u is 1, 2, 3, 4 or 5;    -   v is 2 or 3; and-   whereby each hydrogen atom in Alk and the carbocycles and the    heterocycles defined in radicals (b-3), (b-4), (b-5), (b-6), (b-7)    and (b-8) may optionally be replaced by R³; with the proviso that    when R³ is hydroxy or C₁₋₆alkyloxy, then R³ can not replace a    hydrogen atom in the α position relative to a nitrogen atom;-   G is a direct bond or C₁₋₁₀alkanediyl optionally substituted with    one, two or three substituents selected from hydroxy, C₁₋₆alkyloxy,    arylC₁₋₆ alkyloxy, C₁₋₆ alkylthio, arylC₁₋₆alkylthio, arylcarbonyl,    HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)₀—, arylC₁₋₆    alkyloxy(—CH₂—CH₂—O)_(n)—, amino, mono-or di(C₁₋₆alkyl)amino,    C₁₋₆alkyloxycarbonylamino and aryl;-   R¹ is a bicyclic heterocycle selected from quinolinyl, quinoxalinyl,    benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,    benzthiazolyl, pyridopyridyl, naphthiridinyl,    1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,    imidazo[1,2-a]pyridinyl, 2,3-dihydro-1,4-dioxino[2,3-b]pyridyl or a    radical of formula

-   and said bicyclic heterocycles may optionally be substituted in    either of the two cycles with 1 or where possible more, such as 2, 3    or 4, substituents selected from halo, hydroxy, amino, cyano,    carboxy, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₁₋₆alkyloxy-C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, arylC₁₋₆alkyloxy,    hydroxyC₁₋₆alkyl, mono-or di(C₁₋₆alkyl)amino, mono-or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, polyhaloC₁₋₆alkyl,    C₁₋₆alkylcarbonylamino, C₁₋₆alkyl-SO₂—NR^(5c) , aryl—SO₂—NR^(5c),    C₁₋₆alkyloxycarbonyl, —C(═O)—NR⁵CR^(5d), HO(CH₂—CH₂—O)_(n)—,    halo(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—,    arylC₁₋₆alkyloxy(CH₂—CH₂—O)_(n)— and mono-or    di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—;-   each n independently is 1, 2, 3 or 4;-   each m independently is 1 or 2;-   each p independently is 1 or 2;-   each R² independently is hydrogen, formyl, C₁₋₆alkylcarbonyl,    Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl,    C₃₋₇Cycloalkyl substituted with N(R⁶)₂, or C₁₋₁₀alkyl substituted    with N(R⁶)₂ and optionally with a second, third or fourth    substituent selected from amino, hydroxy, C₃₋₇cycloalkyl,    C₂₋₅alkanediyl, piperidinyl, mono-or di(C₁₋₆alkyl)amino,    C₁₋₆alkyloxycarbonylamino, aryl and aryloxy;-   R³ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆ alkyloxy, arylC₁₋₆alkyl or    arylC₁₋₆alkyloxy;-   R⁴ is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl;-   R^(5a), R^(5b), R^(5c) and R^(5d) each independently are hydrogen or    C₁₋₆alkyl; or-   R^(5a) and R^(5b), or R^(5c) and R^(5d) taken together form a    bivalent radical of formula —(CH₂)_(s)-wherein s is 4 or 5;-   R⁶ is hydrogen, C₁₋₄alkyl, formyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkylcarbonyl or-   C₁₋₆alkyloxycarbonyl;-   aryl is phenyl or phenyl substituted with 1 or more, such as 2, 3 or    4, substituents selected from halo, hydroxy, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, and-   C₁-alkyloxy;-   Het is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.

The term prodrug as used throughout this text means thepharmacologically acceptable derivatives, e.g. esters and amides, suchthat the resulting biotransformation product of the derivative is theactive drug as defined in the compounds of formula (I). The reference byGoodman and Gilman (The Pharmacological Basis of Therapeutics, 8^(th)ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13–15)describing prodrugs generally, is hereby incorporated.

As used herein C₁₋₃alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 3carbon atoms such as methyl, ethyl, propyl, 1-methylethyl and the like;C₁₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as the group defined for C₁₋₃alkyl and butyl and the like;C₂₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 2 to 4 carbon atomssuch as ethyl, propyl, 1-methylethyl, butyl and the like; C₁₋₄alkyl as agroup or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 6 carbon atoms such as the groupsdefined for C₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like;C₁₋₉alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 9 carbon atomssuch as the groups defined for C₁alkyl and heptyl, octyl, nonyl,2-methylhexyl, 2-methylheptyl and the like; C₁₋₁₀alkyl as a group orpart of a group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 10 carbon atoms such as the groups defined forC₁₋₉alkyl and decyl, 2-methylnonyl and the like. C₃₋₇cycloalkyl isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; C₂₋₅alkanediyl defines bivalent straight and branched chainsaturated hydrocarbon radicals having from 2 to 5 carbon atoms such as,for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like,C₂₋₅alkanediyl is substituted on C₁₋₁₀alkyl as provided for in thedefinition of R², it is meant to be substituted on one carbon atom thusforming a spiro moiety; C₁₋₄alkanediyl defines bivalent straight andbranched chain saturated hydrocarbon radicals having from 1 to 4 carbonatoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl and the like; C₁₋₆alkanediyl is meant to includeC₁₋₄alkanediyl and the higher homologues thereof having from 5 to 6carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl andthe like; C₁₋₁₀alkanediyl is meant to include C₁₋₆alkanediyl and thehigher homologues thereof having from 7 to 10 carbon atoms such as, forexample, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl,1,10-decanediyl and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. The term (═N—OH) forms a hydroxylimine moiety when attachedto a carbon atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as mono- or polyhalosubstituted C₁₋₆alkyl, inparticular methyl with one or more fluoro atoms, for example,difluoromethyl or trifluoromethyl. In case more than one halogen atomsare attached to an alkyl group within the definition ofpolyhaloC₁₋₄alkyl, they may be the same or different.

As described hereinabove, R¹ defines a bicyclic heterocycle which mayoptionally be substituted. The substituents may be divided over bothrings or they may be attached to one and the same ring.

When any variable (e.g. aryl, R²,R³, R⁴, R^(5a), R^(5b) etc.) occursmore than one time in any constituent, each definition is independent.

It will be appreciated that some of the compounds of formula (I) andtheir prodrugs, N-oxides, addition salts, quaternary amines, metalcomplexes and stereochemically isomeric forms may contain one or morecenters of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their prodrugs, N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their prodrugs, N-oxides, salts, solvates or quaternaryamines substantially free, i.e. associated with less than 10%,preferably less than 5%, in particular less than 2% and most preferablyless than 1% of the other isomers. Stereochemically isomeric forms ofthe compounds of formula (I) are obviously intended to be embracedwithin the scope of this invention. As used hereinafter the terms transor cis are well-known by the person skilled in the art.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butane-dioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioicacid), tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like. The term “quaternary amine” as used hereinbefore defines thequaternary ammonium salts which the compounds of formula (I) are able toform by reaction between a basic nitrogen of a compound of formula (I)and an appropriate quaternizing agent, such as, for example, anoptionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

It will be appreciated that the compounds of formula (I) may have metalbinding, chelating, complexating properties and therefore may exist asmetal complexes or metal chelates. Such metalated derivatives of thecompounds of formula (I) are intended to be included within the scope ofthe present invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

A special group of corn pounds are those compounds of formula (I)wherein one or more of the following restrictions apply:

-   -   Q is a radical of formula (b-1), (b-3), (b-4), (b-5), (b-6),        (b-7) or (b-8);    -   X² is a direct bond, CH₂ or C(═O);    -   R¹ is a bicyclic heterocycle selected from quinolinyl,        quinoxalinyl, benzofuranyl, benzothienyl, benzimidazolyl,        benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthiridinyl,        1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,        imidazo[1,2-a]pyridinyl, or a radical of formula

and said bicyclic heterocycles may optionally be substituted in eitherof the two cycles with 1 or where possible more, such as 2, 3 or 4,substituents selected from halo, hydroxy, amino, cyano, carboxy,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, aryl,aryl C₁₋₆alkyl, arylC₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, mono-ordi(C₁₋₆alkyl)amino, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆ alkylcarbonylamino, CH₂—CH₂—O)_(n)—,halo(—CH₂—CH₂—O)_(n)-, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, arylC₁₋₆alkyloxy(-CH₂—CH₂—O)_(n),- and mono-or di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)-;

-   each n independently is 1, 2, 3 or 4;-   each m independently is 1 or 2;-   each p independently is 1 or 2;    -   each R² independently is hydrogen, pyrrolidinyl, piperidinyl,        homopiperidinyl, C₃₋₇cycloalkyl substituted with NHR⁶, or        C₁₋₁₀alkyl substituted with NHR⁶ and optionally with a second,        third or fourth substituent selected from amino, hydroxy,-   C₃₋₇cycloalkyl, C₂₋₅alkanediyl, piperidinyl, mono-or    di(C₁₋₆alkyl)amino,-   C₁₋₆alkyloxycarbonylamino, aryl and aryloxy;    -   R³ is hydrogen, hydroxy, C₁-alkyl, C₁₋₆alkyloxy or        arylC₁₋₆alkyl;    -   R⁶ is hydrogen, C₁₋₄alkyl, formyl, C₁₋₆alkylcarbonyl or        C₁₋₆alkyloxycarbonyl.

Another special group of compounds are those compounds wherein-a¹=a²-a³=a⁴- is a radical of formula (a-1), (a-2) or (a-3).

Yet another special group of compounds are those compounds wherein Q isa radical of formula (b-5) wherein v is 2, and Y¹ is NR².

Also interesting compounds are those compounds wherein R² is C₁₋₁₀alkylsubstituted with NHR⁶.

Other interesting compounds are those compounds wherein G is a directbond or C₁₋₁₀alkanediyl optionally substituted with one two or threesubstituents selected from hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy,HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂)_(n)—,arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—.

Preferred compounds are:

-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-4-methyl-1-[1-(8-quinolinyl)ethyl]-1H-benzimidazol-2-amine    monohydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(2-bromo-5,6,7,8-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine    trihydrochloride trihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]4-methyl-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine    trihydrochloride trihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(ethoxy-8-quinolinylmethyl)-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-4-methyl-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-7-methyl-3-(8-quinolinylmethyl)-3H-imidazo-[4,5-b]pyridin-2-amine    tetrahydrochloride trihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-7-methyl-3-(8-quinolinylmethyl)-3H-imidazo-[4,5-b]pyridin-2-amine    tetrahydrochloride monohydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(8-quinolinylmethyl)-1H-imidazo[4,5-c]pyridin-2-amine    trihydrochloride dihydrate;-   N-[1-(2-aminoethyl)₄-piperidinyl]4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;-   N-[1-(8-quinolinylmethyl)-1H-benzimidazol-2-yl]-1,3-propanediamine    trihydrochloride monohydrate;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine    trihydrochloride dihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(8-quinolinylmethyl)-1H-imidazo[4,5-b]pyridine-2-amine    trihydrochloride dihydrate;-   (±)-N-[1-[1-(aminomethyl)-2-methylpropyl]4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-3-(2-quinolinylmethyl)-3H-imidazo-[4,5-b]pyridin-2-amine    trihydrochloride trihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(1-isoquinolinylmethyl)-1H-benzimidazol-2-amine    trihydrochloride trihydrate;-   N-[1-(2-aminoethyl)₄-piperidinyl]-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine    trihydrochloride trihydrate;-   the prodrugs, the N-oxides, the addition salts, the quaternary    amines, the metal complexes and the stereochemically isomeric forms    thereof.    Most preferred compounds are:-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-3-(quinolinylmethyl)-3H-imidazo[4,5b]pyridin-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]    4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)₄-methyl-1H-benzimidazol-2-amine    trihydrochloride-trihydrate;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-1-(5,6,7,8-tetrahydro-2,3-dimethyl-5-quinoxalinyl)-1H-benzimidazol-2-amine    trihydrochloride trihydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinyl-methyl]-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine    trihydrochloride monohydrate;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)₄-methyl-1H-benzimidazol-2-amine    trihydrochloride dihydrate;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]4-methyl-1H-benzimidazol-2-amine    monohydrate;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-3-(8-quinolinylmethyl)-3H-imidazo[4,5-c]pyridin-2-amine    trihydrochloride tetrahydrate;-   (±)-N-[1-(2-aminoethyl)₄-piperidinyl]-3-(8-quinolinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]4-methyl-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;-   (±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)₄-methyl-1H-benzimidazol-2-amine;    the prodrugs, the N-oxides, the addition salts, the quaternary    famines, the metal complexes and the stereochemically isomeric forms    thereof.

In general, compounds of formula (I) can be prepared by reacting anintermediate of formula (II-a) or (II-b), wherein P represents aprotecting group, such as, for example C₁₋₄alkyloxycarbonyl, or thoseprotecting groups mentioned in Chapter 7 of ‘Protective Groups inOrganic Synthesis’ by T Greene and P. Wuyts (John Wiley & Sons Inc.,1991), with an intermediate of formula (III), wherein W₁ is a suitableleaving group, such as a halo atom, e.g. chloro, bromo, in the presenceof a suitable base, such as, e.g. sodium hydride. Said reaction can beperformed in a reaction-inert solvent, such as N,N-dimethylformamide.

Compounds of formula (I) wherein, in the definition of Q, R² or at leastone R⁶ substituent is hydrogen, said Q being represented by H-Q₁, andsaid compounds being represented by formula (I-a), can be prepared bydeprotecting an intermediate of formula (IV) wherein P represents aprotecting group, for example C] ₄alkyloxycarbonyl, benzyl, or thoseprotecting groups mentioned in Chapter 7 of ‘Protective Groups inOrganic Synthesis’ by T Greene and P. Wuyts (John Wiley & Sons Inc.,1991).

When P represents, for example, C₁₋₄alkyloxycarbonyl, said deprotectionreaction can be performed by, for example, acidic hydrolysis in thepresence of a suitable acid, such as hydrobromic, hydrochloric,sulfuric, acetic, or trifluoroacetic acid or a mixture of said acids, orby alkaline hydrolysis in the presence of a suitable base, such as, forexample potassium hydroxide, in a suitable solvent such as water,alcohol, a mixture of water-alcohol, methylene chloride. Suitablealcohols are methanol, ethanol, 2-propanol, 1-butanol and the like. Inorder to enhance the rate of the reaction, it is advantageous to heatthe reaction mixture, in particular up to the reflux temperature.Alternatively, when P represents, for example, benzyl, the deprotectionreaction can be performed by catalytic hydrogenation in the presence ofhydrogen and an appropriate catalyst in a reaction-inert solvent. Asuitable catalyst in the above reaction is, for example,platinum-on-charcoal, palladium-on-charcoal, and the like. Anappropriate reaction-inert solvent for said reaction is, for example, analcohol, e.g. methanol, ethanol, 2-propanol and the like, an ester, e.g.ethylacetate and the like, an acid, e.g. acetic acid and the like.

The catalytic hydrogenation reaction described above can also be used toprepare a compound of formula (I-a) by deprotecting and reducing anintermediate of formula (IV) wherein Q₁ comprises an unsaturated bond,said Q₁ being represented by Q_(1a)(CH═CH), and said intermediate beingrepresented by formula (IV-a).

Compounds of formula (I) wherein, in the definition of Q, both R⁶substituents are hydrogen or R² and R⁴ are both hydrogen, said Q beingrepresented by H₂N-Q₂, and said compounds being represented by formula(I-a-1), can also be prepared by deprotecting an intermediate of formula(V).

Said deprotection reaction can be performed in the presence of asuitable base such as, for example hydrazine, or in the presence of asuitable acid, such as hydrochloric acid and the like, in a suitablesolvent, such as an alcohol, acetic acid and the like. Compounds offormula (I-a-1) can also be prepared by deprotecting an intermediate offormula (VI) according to the procedure described for the preparation ofcompounds of formula (I-a).

Compounds of formula (I-a) or (I-a-1), wherein Q₁ or Q₂ comprise ahydroxy substituent, said Q₁ or Q₂ being represented by Q_(1′)(OH) orQ_(2′)(OH), and said compounds being represented by formula (I-a-2) or(I-a-1-1), can be prepared by deprotecting an intermediate of formula(VII) or (VIII) as described hereinabove for the preparation ofcompounds of formula (I-a).

Compounds of formula (I) wherein, in the definition of Q, both R⁶substituents are hydrogen or R² and R⁴ are both hydrogen, and the carbonadjacent to the nitrogen carrying the R⁶, or R² and R⁴ substituentscontains at least one hydrogen, said Q being represented by H₂N-Q₃H, andsaid compounds being represented by formula (I-a-1-2) can also beobtained by reductive amination of intermediates of formula (IX) in thepresence of a suitable amination reagent, such as, for example, ammonia,hydroxylamine, or benzylamine, and in the presence of a suitablereducing agent, e.g. hydrogen, and an appropriate catalyst. Anappropriate catalyst in the above reaction is, for example,platinum-on-charcoal, palladium-on-charcoal, rhodium-on-Al₂O₃, and thelike, optionally in the presence of a catalyst poison, such as athiophene solution. A suitable reaction-inert solvent for the abovereaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanoland the like.

Compounds of formula (I), wherein Q comprises a —CH₂NH₂ moiety, said Qbeing represented by H₂N—CH₂—Q₄, and said compounds being represented byformula (I-a-1-3) can be prepared by reducing an intermediate of formula(X).

Said reduction can be performed with a suitable reducing agent, such aslithium aluminium hydride or hydrogen, optionally in the presence of asuitable catalyst, such as Raney Nickel. A suitable solvent for theabove reaction is, for example, tetrahydrofuran, or a solution ofammonia in an alcohol. Suitable alcohols are methanol, ethanol,2-propanol and the like. Said reduction reaction performed in a solutionof ammonia in an alcohol can also be used to prepare compounds offormula (I-a-1-3), wherein R¹ is substituted with C₁₋₆alkyloxyC₁₋₆alkyl,said R¹ being represented by R¹″—C₁₋₆alkyloxyC₁₋₆alkyl, and saidcompounds being represented by formula (I-a-1-3-1) starting from anintermediate of formula (X-a).

Compounds of formula (I), wherein Q comprises a —CH₂—CHOH—CH₂—NH₂moiety, said Q being represented by H₂N—CH₂—CHOH—CH₂—Q₄′, and saidcompounds being represented by formula (I-a-1-3-2), can be prepared byreacting an intermediate of formula (XI) with ammonia in the presence ofa suitable reaction-inert solvent, such as an alcohol, e.g. methanol.

Compounds of formula (I), wherein, in the definition of Q, R² or one R⁶substituent is formyl, said Q being represented by H—C(═O)-Q₁, and saidcompounds being represented by formula (I-b), can be prepared byreacting an intermediate of formula (XII) with formic acid, formamideand ammonia.

Compounds of formula (I), wherein, in the definition of Q, R² is otherthan hydrogen, said R² being represented by R^(2a) R⁴ is hydrogen, andthe carbon atom adjacent to the nitrogen atom carrying the R and R⁴substituents, carries also at least one hydrogen atom, said Q beingrepresented by R²-NH-HQ₅, and said compounds being represented byformula (I-c), can be prepared by reductive amination of an intermediateof formula (XIII) with an intermediate of formula (XIV) in the presenceof a suitable reducing agent, such as hydrogen, and a suitable catalyst,such as palladium-on-charcoal, platinum-on-charcoal, and the like. Asuitable reaction-inert solvent for the above reaction is, for example,an alcohol, e.g. methanol, ethanol, 2-propanol and the like.

Compounds of formula (I-c), wherein R^(2a) represents C₁₋₁₀alkylsubstituted with N(R⁶)₂ and with hydroxy, and the carbon atom carryingthe hydroxy, carries also two hydrogen atoms, said R²′ being representedby [(C₁₋₉alkyl)CH₂OH]—N(R⁶)₂, and said compounds being represented byformula (I-c-1), can be prepared by reducing an intermediate of formula(XV) in the presence of a suitable reducing agent, such as lithiumaluminium hydride, in a suitable reaction-inert solvent, such astetrahydrofuran.

Compounds of formula (I) wherein, in the definition of Q, R² or one R⁶substituent is hydrogen, said Q being represented by H—Q₁, and whereinR¹ is a bicyclic heterocycle substituted with 1 or more substituentsselected from hydroxy, hydroxyC₁₋₆alkyl, or HO(—CH₂—CH₂—O)_(n)—, saidsubstituents being represented by formula A-OH, said R¹ beingrepresented by R^(1a)—(A—OH)_(w), with w being the amount ofsubstituents on R¹ ranging from 1 to 4, and said compounds beingrepresented by formula (I-d), can be prepared by deprotecting anintermediate of formula (XVI) with a suitable acid, such as hydrochloricacid and the like, optionally in the presence of a suitable solvent,such as an alcohol. Suitable alcohols are methanol, ethanol, 2-propanoland the like. Alternatively, one protecting group may also protect morethan one substituent of R^(1a), said protecting group being representedby P₁, as represented by formula (XVI-a). The two ways of protecting thesubstituents of R_(1a), i.e. with a separate, as in formula (XVI), or acombined, as in formula (XVI-a), protecting group, may also be combinedin the same intermediate, as represented by formula (XVI-b).

Compounds of formula (I), wherein Q is a radical of formula (b-2), saidcompounds being represented by formula (I-e), can be prepared byreacting an intermediate of formula (XVIII) with an intermediate offormula (XVIII) in the presence of sodium cyanide and a suitablereaction-inert solvent, such as an alcohol, e.g. methanol and the like.

Compounds of formula (I), wherein in the definition of Q, X² isC₂₋₄alkyl—NR⁴, said Q being represented by Q₆N—CH₂—C₁₋₃alkyl-NR, andsaid compounds being represented by formula (I-p), can be prepared byreacting an intermediate of formula (XIX) with an intermediate offormula (XX) in the presence of isopropyl titanate (IV) and a suitablereducing agent, such as NaBH₃CN, and in the presence of a suitablereaction-inert solvent, such as methylene chloride and an alcohol, e.g.ethanol.

Compounds of formula (I-p), wherein R² is C₁₋₆alkylcarbonyl, and Q is aradical of formula (b-6), wherein Y¹ is NR², said compounds beingrepresented by formula (I-p-1), can be prepared by reacting anintermediate of formula (XIX) with an intermediate of formula (XX-a)according to the procedure described for the preparation of a compoundof formula (I-p).

Compounds of formula (I), wherein G is substituted with hydroxy orHO(—CH₂CH₂O)_(n)—, said G being represented by G₁—OH, and said compoundsbeing represented by formula (I-q), may be prepared by deprotecting anintermediate of formula (XXI), wherein P represents a suitableprotecting group, for example, benzyl. Said deprotection reaction can beperformed by catalytic hydrogenation in the presence of hydrogen and anappropriate catalyst in a reaction-inert solvent. A suitable catalyst inthe above reaction is, for example, platinum-on-charcoal,palladium-on-charcoal, and the like. An appropriate reaction-inertsolvent for said reaction is, for example, an alcohol, e.g. methanol,ethanol, 2-propanol and the like, an ester, e.g. ethylacetate and thelike, an acid, e.g. acetic acid and the like.

Compounds of formula (I), wherein G is substituted with hydroxy and thecarbon atom carrying the hydroxy substituent carries also at least onehydrogen, said G being represented by H—G₂-OH, and said compounds beingrepresented by formula (I-q-1), can also be prepared by reducing anintermediate of formula (XXII).

Said reduction reaction can be performed in the presence of a suitablereducing agent, such as, for example sodium borohydride, in areaction-inert solvent, such as an alcohol or tetrahydrofuran or amixture thereof. Suitable alcohols are methanol, ethanol, 2-propanol andthe like.

Compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions, comprising thosedescribed hereinafter.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise; for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboper-oxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo-peroxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t-butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I), wherein R¹ is a bicyclic heterocyclesubstituted with C₁₋₆alkyloxycarbonyl, said R¹ being represented byR^(1′)—C(═O)OC₁₋₆alkyl, and said compounds being represented by formula(I-f), can be prepared by esterification of a compound of formula (I-g)in the presence of a suitable alcohol, e.g. methanol, ethanol, propanol,butanol, pentanol, hexanol and the like, and in the presence of asuitable acid, such as hydrochloric acid and the like.

Compounds of formula (I-a) may be converted into compounds of formula(I) wherein, in the definition of Q, R² or at least one R⁶ substituentis other than hydrogen, said R or R⁶ being represented by Z₁, said Qbeing represented by Z₁—Q₁, and said compounds being represented byformula (I-h), by reaction with a reagent of formula (XXIII), wherein W₂is a suitable leaving group, such as a halo atom, e.g. bromo, or4-methylbenzenesulphonate, in the presence of a suitable base, such as,for example disodium carbonate, dipotassium carbonate, sodium hydroxideand the like, in a reaction-inert solvent, e.g. 3-methyl-2-butanone,acetonitrile, N,N-dimethylformamide.

Compounds of formula (I-h), wherein, in the definition of Z¹, R² isCH₂—C₁₋₉alkyl substituted with N(R⁶)₂, said compounds being representedby formula (I-h-1), can also be prepared by reacting a compound offormula (I-a) wherein, in the definition of H-Q₁,

-   R² is hydrogen, said H-Q₁ being represented by H-Q_(1b), and said    compounds being represented by formula (I-a-3), with an intermediate    of formula (XXIV), in the presence of a suitable reducing agent,    such as sodium cyanoborohydride, in a suitable reaction-inert    solvent, such as an alcohol.

Compounds of formula (I-h), wherein Z₁ comprises formyl,C₁₋₆alkylcarbonyl, Hetcarbonyl or C₁₋₆alkyloxycarbonyl, said Z₁ beingrepresented by Z_(1a), and said compounds being represented by formula(I-h-2), can be converted into compounds of formula (I-a), by acidichydrolysis in the presence of a suitable acid, such as hydrobromic,hydrochloric, sulfuric, acetic, or trifluoroacetic acid or a mixture ofsaid acids, or by alkaline hydrolysis in the presence of a suitablebase, such as, for example potassium hydroxide, in a suitable solventsuch as water, alcohol, a mixture of water-alcohol, methylene chloride.Suitable alcohols are methanol, ethanol, 2-propanol, 1-butanol, sec.butanol and the like. In order to enhance the rate of the reaction, itis advantageous to work at elevated temperatures.

Compounds of formula (I-b) can be prepared by reacting a compound offormula (I-a) with formic acid.

Compounds of formula (I) wherein R₁ is a bicyclic heterocyclesubstituted with hydroxy, said R¹ being represented by HO—R¹⁻, and saidcompounds being represented by formula (I-i), can be prepared bydeprotecting a compound of formula (I-j), wherein R¹ is a bicyclicheterocycle substituted with C₁₋₆alkyloxy or arylC₁₋₆alkyloxy, saidC₁₋₆alkyl or arylC₁₋₆alkyl being represented by Z₂, and said R¹ beingrepresented by Z₂—O—R¹⁻. Said deprotection can be performed in areaction-inert solvent, such as, for example methylene chloride, in thepresence of a suitable deprotecting agent, e.g. tribromoborane.

Compounds of formula (I) wherein R¹ is a bicyclic heterocyclesubstituted with halo(—CH₂—CH₂—O)_(n), said compounds being representedby formula (I-k), can be converted into compounds of formula (I-1-1) or(I-1-2) by reaction with an appropriate amine of formula (XXV) or (XXVI)in a suitable reaction-inert solvent, e.g. tetrahydrofuran.

Compounds of formula (I) wherein R¹ is a bicyclic heterocyclesubstituted with halo, said compounds being represented by formula (I-m)can be converted into compounds of formula (I) by reaction with1-butanethiol in the presence of palladium-on-charcoal and CaO in asuitable reaction-inert solvent, such as tetrahydrofuran.

Compounds of formula (I) wherein a hydrogen atom in the radicals offormula (a-1), (a-2), (a-3), (a-4) or (a-5) is replaced by nitro, saidcompounds being represented by formula (I-n) may be reduced to acompound of formula (I-o) in the presence of a suitable reducing agent,such as hydrogen, optionally in the presence of a suitable catalyst,such as platinum-on-charcoal, and optionally in the presence of asuitable catalyst poison, e.g. a thiophene solution. The reaction may beperformed in a suitable reaction-inert solvent, such as an alcohol.

In the following paragraphs, there are described several methods ofpreparing the intermediates in the foregoing preparations. A number ofintermediates and starting materials are commercially available or areknown compounds which may be prepared according to conventional reactionprocedures generally known in the art or analogous to the proceduresdescribed in EP-A-0005318, EP-A-0099139, EP-A-0151824, EP-A-0151826,EP-A-0232937, EP-A-0295742, EP-A-0297661, EP-A-0539420, EP-A-0539421,U.S. Pat. No. 4,634,704, U.S. Pat. No. 4,695,569.

In the foregoing and the following preparations, the reaction mixture isworked up following art-known methods and the reaction product isisolated and, if necessary, further purified.

Intermediates of formula (E) can be prepared by reacting an intermediateof formula (XXVII) with a suitable leaving group, i.e. W₁, introducingagent, e.g. 1-halo-2,5-pyrrolidinedione in the presence of dibenzoylperoxide, in a reaction-inert solvent, e.g. tetrachloromethane.

Intermediates of formula (XXVI), wherein R¹ is a bicyclic heterocyclesubstituted with chloro, said R¹ being represented by Cl—R^(1′) and saidintermediates being represented by formula (XXVII-a) can be prepared byreacting an intermediate of formula (XXVIII), wherein (O═)R^(1b)H isdefined as a carbonyl derivative of R¹⁻ wherein one carbon or nitrogen,adjacent to the carbonyl, carries at least one hydrogen, with phosphorusoxychloride. Intermediates of formula (XXVIII) may also react as theirenol tautomeric forms.

Intermediates of formula (XXVII), wherein R¹ is2-trifluoromethyl-3-methyl (3H)imidazo[4,5-b]pyridine, and G is CH₂,said intermediates being represented by formula (XXVII-b), can beprepared by reacting N-2,6-dimethyl-2,3-pyridinediamine (Heterocycles,38, p 529, 1994), with trifluoroacetic acid.

Intermediates of formula (III) wherein W₁ is chloro, which is attachedto a carbon atom carrying at least one hydrogen, said Gi beingrepresented by G₃H, and said intermediates being represented by formula(ff-a) can also be prepared by reacting an intermediate of formula(XXIX) with thionylchloride in a reaction-inert solvent, e.g.methylenechloride.

Intermediates of formula (XXIX) can be prepared by reducing anintermediate of formula (XXX) in a reaction-inert solvent, e.g. analcohol, in the presence of a suitable reducing agent, e.g. sodiumborohydride.

Alternatively, intermediates of formula (XXIX) can also be prepared bydeprotecting an intermediate of formula (XXXI), wherein P is a-suitableprotecting group, e.g. C₁₋₄alkylcarbonyl, in a reaction-inert solvent,such as an alcohol, in the presence of a suitable base, e.g. sodiumhydroxide.

Intermediates of formula (XXX), wherein G₃(═O) is CH(═O), saidintermediates being represented by formula (XXX-a), can be prepared byreacting an intermediate of formula (XXXII), wherein W₃ is a suitableleaving group, such as a halo atom, e.g. bromo, withN,N-dimethylformamide in the presence of butyllithium in areaction-inert solvent, e.g. tetrahydrofuran, diethylether or a mixturethereof.

Intermediates of formula (XXX-a) can also be prepared by oxidizing anintermediate of formula R¹—CH₂—OH in the presence of a suitableoxidizing agent, e.g. MnO₂ in a reaction-inert solvent, e.g.methylenechloride.

Intermediates of formula R₁—CH₂—OH, wherein R¹ is2,3-dimethylquinoxaline, said intermediates being represented by formula(XCI) can be prepared by reducing an intermediate of formula (XCII) in areaction-inert solvent, e.g. tetrahydrofuran, in the presence of asuitable reducing agent, e.g. potassium borohydride in the presence oflithium chloride.

Intermediates of formula (XCII) can be prepared by reacting ethyl2,3-diaminobenzoate (Tetrahydron, 28, 3271, 1972) with 2,3-butanedionein the presence of disodium disulfite.

Intermediates of formula (XXXI), wherein R¹ is5,6,7,8-tetrahydroquinoline, which can optionally be substituted, G₃H isCH₂, and P is C₁₋₄alkylcarbonyl, said intermediates being represented byformula (XXXI-a) can be prepared by reacting an intermediate of formula(XCIII) with C₁₋₄alkylacid anhydride at elevated temperatures in thepresence of a suitable base, e.g. sodium hydroxide.

Intermediates of formula (XCIII) can be prepared by oxidizing anintermediate of formula (XCIV) with a suitable oxidizing agent, e.g. aperoxide such as 3-chloro-benzenecarboperoxoic acid, in a reaction-inertsolvent, e.g. methylene chloride.

Intermediates of formula (XCIV) can be prepared by reducing anintermediate of formula (XCV) (Org. Prep. Proced. Int., 23, p 386–387,1991) with an appropriate reducing agent, e.g. hydrogen, in the presenceof a suitable catalyst, e.g. palladium-on-charcoal, and a suitable acid,e.g. trifluoroacetic acid.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (XXXII-a) or (XXXI-b), wherein P represents asuitable protecting group, such as, for example, C₁₋₄alkyloxycarbonyl,with an intermediate of formula (E) according to the reaction describedfor the general preparation of compounds of formula (I).

Intermediates of formula (IV) can also be prepared by reacting anintermediate of formula (XXXIII-a) with an intermediate of formula(XXXIV) that has reacted with methanesulfonyl chloride, in the presenceof a suitable base, such as sodium hydride, and in the presence of asuitable reaction-inert solvent, e.g. N,N-dimethylformamide.

Intermediates of formula (IV) can also be prepared by a cyclizationreaction of an intermediate of formula (XXXV) in a reaction-inertsolvent, e.g. an alcohol or N,N-dimethylformamide, in the presence ofmercury oxide and sulphur.

Intermediates of formula (IV) wherein Q₁ comprises an unsaturated bond,said Q₁ being represented by Q_(1a)(CH═CH), and said intermediates byformula (IV-a), can be prepared by reacting an intermediate of formula(XXXVI) with an intermediate of formula (III) in the presence of asuitable base, such as dipotassium carbonate.

Intermediates of formula (TV) wherein, in the definition of Q₁, the X¹or X² moieties in the radicals of formula (b-1) to (b-8) represent NH,said Q, being represented by Q_(1c)—NH, and said intermediates byformula (IV-b), may also be prepared by reacting an intermediate offormula (XXXVII) with an intermediate of formula (XXXVIII).

Intermediates of formula (IV) wherein R¹ is a bicyclic heterocyclesubstituted with amino or mono- or di(C₁₋₆alkyl)amino, said R¹ beingrepresented by R_(5a)R_(5b)N—R¹, wherein R^(5a) and R^(5b) are definedas described above, and said intermediates being represented by formula(IV-c), can be prepared by reacting an intermediate of formula (XXXIX)with an appropriate amine, represented by formula (XL), in the presenceof an appropriate catalyst, e.g. palladium, and(R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphtyl, in a suitablereaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV) wherein R¹ is a bicyclic heterocyclesubstituted with C(═O)—NR^(5a)R^(5b), wherein R^(5a) and R^(5b) aredefined as described above, said R¹ being represented byR^(5a)R⁵>N—C(═O)—R^(1′), and said intermediates being represented byformula (IV-d), can be prepared by reacting an intermediate of formula(XXXIX) with an appropriate amine, represented by formula (XL), under anatmosphere of carbon monoxide, in the presence of a suitable catalyst,e.g. palladium (II) acetate, and 1,3-bis(diphenylphosphino)propane, in asuitable reaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (TV) wherein P-Q₁ comprises C₁₋₁₀alkyl orC₃₋₇cycloalkyl substituted with NR⁶—P, said C₁₋₁₀alkyl or C₃₋₇cycloalkylbeing represented by Z₃, said P-Q₁ being represented by P—NR⁶—Z₃—Q_(1b),and said intermediates being represented by formula (IV-e), can beprepared by reacting a compound of formula (I-a-3) with an intermediateof formula (XU), wherein W₄ represents a suitable leaving group, such asp-toluenesulphonate. Said reaction can be performed in a reaction-inertsolvent, e.g. acetonitrile, in the presence of a suitable base, e.g.dipotassium carbonate.

Intermediates of formula (IV-e), wherein R⁶ is hydroxyC₁-alkyl, saidintermediates being represented by formula (IV-e-1), can be prepared byreacting an intermediate of formula (XLII) with an intermediate offormula (XLIII) in the presence of a suitable base, e.g. dipotassiumcarbonate, and a suitable solvent, e.g. acetonitrile.

Intermediates of formula (XXXIII-a) or (XXXIII-b) can be prepared byprotecting an intermediate of formula (XLIV) with a suitable protectinggroup, such as, for example, C₁₋₄alkyloxycarbonyl, in a reaction-inertsolvent, such as methylene chloride or an alcohol, e.g. methanol,ethanol, 2-propanol and the like, in the presence of a suitable reagent,e.g. di C₁₋₄alkyl dicarbonate and optionally in the presence of asuitable base, e.g. sodium acetate.

Alternatively, intermediates of formula (XXXII-a) or (XXXIII-b) can beconverted into an intermediate of formula (XLIV) by reaction with asuitable acid, such as hydrochloric acid or hydrobromic acid and thelike or mixtures thereof, in the presence of a suitable solvent, e.g.water.

Inter-mediates of formula (XXXII-a) or (XXXII-b), wherein in thedefinition of Q₁, the X¹ or X² moieties in the radicals of formula (b-1)to (b-8) represent NH, said Q₁ being represented by Q_(1c)—NH, and saidintermediates by formula (XXXII-a-1) or (XXXIII-b-1), can be prepared byreacting an intermediate of formula (XLV-a) or (XLV-b), wherein W₅represents a suitable leaving group, such as for example a halo atom,e.g. chloro, with an intermediate of formula (XLVI).

Intermediates of formula (XLV-a) or (XLV-b) can be prepared by reactingan intermediate of formula (XLVII-a) or (XLVI-b) with H₂P(═O)(W₅)₃ inthe presence of a suitable acid, e.g. hydrochloric acid.

Intermediates of formula (XLVII-a) or (XLVII-b) can be prepared byreacting an intermediate of formula (XLVIII-a) or (XLVIII-b) with anintermediate of formula (IL).

Intermediates of formula (XXXIII-a) can also be prepared by reacting anintermediate of formula (XLVIII-a) with P-Q₁ —C(═NH)—O—CH₂—CH₃ in areaction-inert solvent, such as an alcohol.

Intermediates of formula (XXXV) can be prepared by reacting anintermediate of formula (L) with an intermediate of formula P—Q₁═C═S,which is synthesized according to the procedures described in EP0005318, in a reaction-inert solvent, such as an alcohol, e.g. ethanol.To increase the reaction rate, the reaction may be performed at elevatedtemperatures.

Intermediates of formula (L) can be obtained by reducing an intermediateof formula (LI) in a reaction-inert solvent, e.g. an alcohol, in thepresence of a suitable reducing agent, e.g. hydrogen, and an appropriatecatalyst, e.g. Raney Nickel.

Intermediates of formula (LI) can be prepared by reacting anintermediate of formula (LII) with an intermediate of formula (LIII), inwhich W₆ represents a suitable leaving group, such as a halo atom, e.g.chloro. This reaction may be performed in a reaction-inert solvent, e.g.acetonitrile, in the presence of a suitable base, e.g. dipotassiumcarbonate.

Intermediates of formula (LII) can be prepared by reacting anintermediate of formula (LIV) with a suitable acid, such as hydrochloricacid, in the presence of a suitable solvent, e.g. an alcohol, e.g.ethanol.

Intermediates of formula (LIV) can be prepared by reacting anintermediate of formula (m) with NaN[C(═O)H]₂.

Intermediates of formula (LI) can also be prepared by reacting anintermediate of formula (LIII) with an intermediate of formula (LV) (J.Org. Chem., 25, p 1138, 1960) in a reaction-inert solvent, e.g.N,N-dimethylformamide, in the presence of an appropriate base, e.g.sodium hydride.

Intermediates of formula (XXXVI) can be prepared by dehydrating anintermediate of formula (LVI) with a suitable acid, such as sulfuricacid.

Intermediates of formula (LVI) wherein, in the definition Of Q_(1a), theX¹ or X² moieties are CH₂, said Q_(1a) being represented by Q_(1a′), andsaid inter-mediates being represented by formula (LVI-a), can beprepared by reacting a carbonyl moiety of formula (LVII) with anintermediate of formula (LVII) in the presence of Nd N-diisopropylamineand butyl lithium, in a suitable reaction-inert solvent, e.g.tetrahydrofuran.

Intermediates of formula (IV), wherein G is C₁₋₁₀alkanediyl substitutedwith C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, HO(—CH₂CH₂O)_(n)—,C₁₋₆alkyloxy(—CH₂CH₂O)_(n)—, or arylC₁₋₆alkyloxy(—CH₂CH₂O)_(n)—, saidgroup of substituents being represented by O-Z₄, said G beingrepresented by Z-O-G₁, and said intermediates being represented byformula (IV-f), can be prepared by reacting an intermediate of formula(XXXIII-a), with an intermediate of formula (LIX), optionally in thepresence of a suitable acid, such as p-toluenesulfonic acid and thelike, and optionally in the presence of a suitable solvent, such asN,N-dimethylacetamide. To increase the reaction rate, the reaction maybe carried out at elevated temperatures.

Intermediates of formula (LIX) can be prepared by reacting anintermediate of formula (LX) with a reagent of formula (LXI) or (LXII)in a reaction-inert solvent, such as an alcohol, or toluene, in thepresence of an acid; e.g. 4-methylbenzenesulphonic acid.

Intermediates of formula (LX) can be prepared by oxidizing anintermediate of formula (LXIII) with a suitable oxidizing agent, e.g.MnO₂, in a reaction-inert solvent, such as methylene chloride.

Intermediates of formula (IV-f) can also be prepared by reacting anintermediate of formula (IV) wherein G is C₁₋₁₀alkanediyl substitutedwith hydroxy, said G being represented by G₁—OH, and said intermediatesbeing represented by formula (Iv-g), with an intermediate of formula(LXIV), wherein W₇ is a suitable leaving group, such as a halo atom,e.g. iodo, in the presence of a suitable base, e.g. sodium hydride, in areaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV-g), wherein the carbon atom of G₁ carryingthe hydroxy, also carries a hydrogen atom, said G₁—OH being representedby H-G₂-OH, and said intermediates being represented by formula(IV-g-1), can be prepared by reducing an intermediate of formula (LXV)in the presence of a suitable reducing agent, e.g. sodium borohydride,in a reaction-inert solvent, such as an alcohol, tetrahydrofuran or amixture thereof. Intermediates of formula (LXV) can also first bedeprotected, e.g. in the presence of a suitable acid, such ashydrochloric acid and the like, resulting in intermediates of formula(LXVI), followed by a reduction, resulting in a compound of formula(I-q-1) wherein Q represents H-Q₁, said compounds being represented byformula (I-q-1-1).

Intermediates of formula (IV), wherein G is ethyl substituted withhydroxy, said intermediates being represented by formula (IV-g-2) canalso be prepared by reacting an intermediate of formula (XXXII-a) withan intermediate of formula (LXVII) in the presence of a suitable base,such as sodium hydride, in a reaction-inert solvent, such asN,N-dimethylformamide.

A subgroup of intermediates of formula (IV-g-2), represented by formula(IV-g-2-1), can also be prepared by reacting an intermediate of formula(LXVIII) with an intermediate of formula (LX) in the presence of1,3-dicyclohexylcarbodiimide, in a reaction-inert solvent, e.g. toluene.

Intermediates of formula (LXV) can be prepared by reacting anintermediate of formula (XXXII-a) with an intermediate of formula (LXX),wherein W₈ is a suitable leaving group, such as a halo atom, e.g. bromo,in the presence of a suitable base, e.g. sodium hydride, in areaction-inert solvent, e.g. N,N-dimethylformamide.

Intermediates of formula (V) can be prepared by reacting an intermediateof formula (LXXI) with 1H-isoindole-1,3 (2H)-dione in the presence oftriphenylphosphine and diethyl azodicarboxylate.

Intermediates of formula (V) may also be prepared by reacting anintermediate of formula (LXXII) with 1H-isoindole-1,3 (2H)-dione in thepresence of a suitable base, such as sodium hydride, and a suitablesolvent, such as N,N-dimethylformamide.

Intermediates of formula (LXXI) can be prepared by reacting anintermediate of formula (LXXI) with an intermediate of formula (LXXIII),wherein W₉ represents a suitable leaving group, such as a halo atom,e.g. chloro, in the presence of a suitable base, such asN,N-diethyl-ethanamine, and a suitable solvent, such as methylenechloride.

Intermediates of formula (V), wherein in the definition Of Q₂, R² isC₁₋₁₀alkyl, said Q₂ being represented by C₁₋₁₀alkyl-Q_(1b), and saidintermediates by formula (V-a), can be prepared by reacting a compoundof formula (I-a-3) with an intermediate of formula (LXXIV), wherein W₁₀is a suitable leaving group, such as a halo atom, e.g. chloro, in thepresence of a suitable base, such as dipotassium carbonate, and asuitable solvent, such as acetonitrile.

Intermediates of formula (LXXI) wherein, in the definition of Q₂, thecarbon atom carrying the hydroxy, also carries two hydrogen atoms, saidHO-Q₂ being represented by HO—CH₂—Q_(2′), and said intermediates beingrepresented by formula (LXX-a), can be prepared by reducing anintermediate of formula (LXXV) in the presence of a suitable reducingagent, such as lithium aluminium hydride, in a suitable reaction-inertsolvent, e.g. tetrahydrofuran.

Intermediates of formula (LXXI), wherein, in the definition of Q₂, thecarbon atom carrying the hydroxy, carries also at least one hydrogen,said HO-Q₂ being represented by HO-Q₃H, and said intermediates beingrepresented by formula (LXX-b), can be prepared by reducing anintermediate of formula (I) with a suitable reducing agent, e.g. sodiumborohydride, in a reaction-inert solvent, e.g. an alcohol.

Intermediates of formula (VI) wherein, in the definition of Q₂, R² isC₁₋₁₀alkyl substituted with N(P)₂ and the carbon atom adjacent to thenitrogen atom carrying the R² substituent carries also at least onehydrogen atom, said Q₂ being represented by (P)₂N—C₁₋₁₀alkyl-NH-Q_(2a)H,and said intermediates being represented by formula (VI-a), can beprepared by reductive amination of an intermediate of formula (LXXVI)with an intermediate of formula (LXXVII) in the presence of a suitablereductive agent, such as hydrogen, and a suitable catalyst, such aspalladium-on-charcoal, platinum-on-charcoal, and the like, andoptionally in the presence of a suitable catalyst poison, such as athiophene solution. A suitable solvent in this reaction is areaction-inert solvent, such as an alcohol.

Intermediates of formula (LXXVI) can be prepared by deprotecting anintermediate of formula (LXXVIII) in the presence of a suitable acid,such as hydrochloric acid and the like, in a suitable solvent, e.g.water.

Intermediates of formula (IX) may be prepared by deprotecting anintermediate of formula (LXXIX) in the presence of a suitable acid, e.g.hydrochloric acid and the like.

Intermediates of formula (LXXIX) can be prepared by reacting anintermediate of formula (LXXX) with an intermediate of formula (III) inthe presence of a suitable base, e.g. dipotassium carbonate, in asuitable reaction-inert solvent, e.g. acetonitrile.

Intermediates of formula (LXXX) wherein, in the definition Of Q₃, the X¹or X² moiety of the radicals of formula (b-1) to (b-8) represent NH,said Q₃ being represented by Q₃, —NH, arid said inter-mediates beingrepresented by formula (LXXX-a), may be prepared by cyclizing anintermediate of formula (LXXXI) in the presence of mercury oxide andsulphur, in a suitable reaction-inert solvent, e.g. an alcohol.

Intermediates of formula (LXXX) can be prepared by reducing anintermediate of formula (LXXXII) in the presence of a suitable reducingagent, such as hydrogen, in the presence of a suitable catalyst, such aspalladium-on-charcoal, platinum-on-charcoal and the like, in a suitablesolvent, e.g. a mixture of ammonia in alcohol. Suitable alcohols aremethanol, ethanol, 2-propanol and the like.

Intermediates of formula (LXXXII) can be prepared by reacting anintermediate of formula (LXXXIII) with an intermediate of formula(LXXXIV) in a suitable reaction-inert solvent, e.g. ethanol.

Intermediates of formula (IX), wherein, in the definition Of Q₃, R²Comprises C₁₋₁₀alkyl, said Q₃ being represented by C₁₋₁₀alkyl-Q_(1b),and said intermediates being represented by formula (IX-a), can beprepared by reacting a compound of formula (I-a-3) with a reagent offormula (LXXV), wherein (O═)C₁₋₁₀alkyl represents a carbonyl derivativeof C₁₋₁₀alkyl and wherein W₁₁ is a suitable leaving group, such as ahalo atom, e.g. bromo, in a reaction-inert solvent, e.g. acetonitrile,in the presence of a suitable base, e.g. dipotassium carbonate.

Intermediates of formula (X) wherein Q₄ comprises C₁₋₉alkyl, said Q₄being represented by C₁₋₉alkyl-Q_(1b), and said intermediates beingrepresented by formula (X-a), can be prepared by reacting a compound offormula (I-a-3) with a reagent of formula (LXXXVI) wherein W₁₂represents a suitable leaving group, such as a halo atom, e.g. chloro,in a reaction-inert solvent, e.g. 3-methyl-2-butanone, in the presenceof a suitable base, e.g. dipotassium carbonate, sodium bicarbonate andthe like.

Intermediates of formula (X), wherein NC-Q₄ representsNC—(C₁₋₉alkyl)(R⁴)N—C(═O)-Alk-X¹, said intermediates being representedby formula (X-b), can be prepared by reacting an intermediate of formula(LXXXVII) with an intermediate of formula (LXXXVIII) in the presence ofdi-1H-imidazol-2-yl-methanone, a suitable base, such asN,N-diethyl-ethanamine, and a suitable solvent, such as methylenechloride.

Intermediates of formula (XI), wherein Q₄, represents Q_(1b), saidintermediates being represented by formula (XI-a), can be prepared byreacting a compound of formula (I-a-3) with an inter-mediate of formula(LXXXIX), wherein W₁₃ represents a suitable leaving group, such as ahalo atom, e.g. chloro, in the presence of a suitable base, such asdisodium carbonate, and in the presence of a suitable solvent, such as3-methyl-2-butanone.

Intermediates of formula (XIX) can be prepared by reacting anintermediate of formula (XC) with a suitable acid, such as hydrochloricacid.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., countercurrent distribution,liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid, respectively chiral base. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography, in particular liquid chromatographyusing a chiral stationary phase. Said pure stereochemically isomericforms may also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereaction occurs stereospecifically. Preferably if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The compounds of formula (I) show anti viral properties. Viralinfections treatable using the compounds and methods of the presentinvention include those infections brought on by ortho- andparamyxoviruses and in particular by human and bovine respiratorysyncytial virus (RSV).

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. (Antiviral Research (1998), 38, 3142).

Due to their antiviral properties, particularly their anti-RSVproperties, the compounds of formula (I) or any subgroup thereof, theirprodrugs, N-oxides, addition salts, quaternary amines, metal complexesand stereochemically isomeric forms, are useful in the treatment ofindividuals experiencing a viral infection, particularly a RSVinfection, and for the prophylaxis of these infections. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses, in particular therespiratory syncytial virus.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the RSV infection.

The present invention also relates to the use of the present compoundsor any subgroup thereof in the manufacture of a medicament for thetreatment or the prevention of viral infections, particularly RSVinfection.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form ormetal complex, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, particularly, foradministration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin.

The compounds of the present invention may also be administered via oralinhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder, a solution beingpreferred. Any system developed for the delivery of solutions,suspensions or dry powders via oral inhalation or insufflation aresuitable for the administration of the present compounds.

Thus, the present invention also provides a pharmaceutical compositionadapted for administration by inhalation or insufflation through themouth comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Preferably, the compounds of the present inventionare administered via inhalation of a solution in nebulized oraerosolized doses.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” isdefined as diisopropyl ether.

A. Preparation of the intermediate compounds

Example A1

a) Sodium methoxide (0.2 mol) was added to a mixture ofN-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide (0.1 mol) inmethanol (389 ml), the mixture was cooled on an ice bath and stirred for2 hours.

Di-tert-butyldicarbonate (0.1 mol) was added to a cooled mixture on anice bath and then stirred for 18 hours at room temperature. The mixturewas evaporated and suspended in water/DIPE. The residue was filteredoff, washed with water/DIPE and dried. The residue was boiled up inCH₃OH, yielding 17.46 g (55.2%) of 1,1-dimethylethyl4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate; mp. 249.4° C.(interm. 1).

b) A mixture of intermediate (1) (0.05 mol), 2-(chloromethyl)quinolinemonohydrochloride (0.055 mol) and sodium carbonate (0.075 mol) in DMF(250 ml) was stirred at 55° C. overnight. The solvent was evaporated.The residue was taken up in H₂O and CH₂Cl₂. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 97/3 and 95/5). The pure fractions were collected and thesolvent was evaporated. The residue was suspended in DIPE, filtered offand dried, yielding 13.5 g (59%) of 1,1-dimethylethyl4-[[1-(quinolinylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 2).

Example A2

a) A mixture of 5,6,7,8-tetrahydro-2(1H)-quinoxalinone in phosphorylchloride (200 ml) was stirred and refluxed for 3 hours. The solvent wasevaporated. The residue was taken up in ice and CH₂Cl₂. The mixture wasbasified with NH₄OH. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated, yielding 34 g (86%) of2-chloro-5,6,7,8-tetrahydroquinoxaline (interm. 3).

b) A mixture of intermediate (3), 1-bromo-2,5-pyrolidinedione (0.116mol) and dibenzoyl peroxide (1.3 g) in tetrachloromethane (400 ml) wasstirred and refluxed for 35 minutes, brought to room temperature andthen filtered. The reaction was carried out again using the samequantities. The residues were combined. The solvent was evaporated. Theresidue (60 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 85/5; 15–35 μm). Two pure fractions werecollected and their solvents were evaporated, yielding 25 g (43%) of(±)-5-bromo-2-chloro-5,6,7,8-tetrahydroquinoxaline (interm. 4) and 12 g(21%) of (±)-8-bromo-2-chloro-5,6,7,8-tetrahydroquinoxaline.

c) A dispersion of sodium hydride in mineral oil (60%) (0.0518 mol) wasadded portionwise at 5° C. under N₂ flow to a mixture of intermediate(1) (0.0471 mol) in DMF (200 ml). The mixture was stirred at 5° C./10°C. for 1 hour. A solution of intermediate (4) (0.0565 mol) in DMF (50ml) was added dropwise. The mixture was stirred at room temperature for3 hours and poured out into H₂O. The precipitate was filtered off andtaken up in CH₂Cl₂. The organic solution was dried (MgSO₄), filtered andthe solvent was evaporated. The residue (32 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH(NH₄OH 95/5/0.1;20–45 μm). The pure fractions were collected and the solvent wasevaporated, yielding 13.3 g (58%) of (±)-1,1-dimethylethyl4-[[1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 5).

Example A3

a) 2,3-Butanedione (0.0776 mol) was added at room temperature to asolution of sodium pyrosulfite (0.1 mol) in water (75 ml). The mixturewas heated to 70° C. and then added to a solution of ethyl2,3-diaminobenzoate (0.0776 mol) in water (75 ml). The mixture wasstirred at 100° C. for 12 hours, cooled, basified with K₂CO₃ 10% and=extracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (17.5 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc93/7; 20–45 μm). The pure fractions were collected and the solvent wasevaporated, yielding 12 g (67%) of ethyl2,3-dimethyl-5-quinoxalinecarboxylate (interm. 6).

b) Lithium chloride (0.6 mol) was added portionwise at 80° C. to amixture of intermediate (6) (0.06 mol) and potassium tetrahydroborate(0.6 mol) in tetrahydrofuran (300 ml). The mixture was stirred at 80° C.for 5 hours, cooled, poured out into H₂O and extracted with EtOAc. Theorganic layer was separated, washed with H₂O, dried (MgSO₄), filteredand the solvent was evaporated, yielding 10.5 g (91%) of(±)-1,2,3,4-tetrahydro-2,3-dimethyl-5-quinoxaline-methanol (interm. 7).

c) MnO₂ (10 g) was added portionwise at room temperature to a mixture ofintermediate (7) (0.0546 mol) in dichloromethane (500 ml). The mixturewas stirred at room temperature overnight, filtered over celite, washedwith CH₂Cl₂ and the filtrate was evaporated. The product was usedwithout further purification, yielding 7.8 g (77%) of2,3-dimethyl-5-quinoxalinecarboxaldehyde (interm. 8).

d) Sodium tetrahydroborate (0.084 mol) was added portionwise at 5° C. toa mixture of intermediate (8) (0.042 mol) in methanol (100 ml). Themixture was stirred at 5° C. for 30 minutes, hydrolized cold andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated, yielding 6.7 g (85%)2,3-dimethyl-5-quinoxalinemethanol (interm. 9).

e) Thionyl chloride (0.045 mol) was added dropwise at 5° C. to a mixtureof intermediate (9) (0.03 mol) in dichloromethane (50 ml). The mixturewas stirred at room temperature for 2 hours, poured out on ice and K₂CO₃10%. The organic layer was separated, washed with K₂CO₃ 10%, dried(MgSO₄), filtered and the solvent was evaporated. The product was usedwithout further purification, yielding 6.2 g (quant.) of5-(chloromethyl)-2,3-dimethyl-quinoxaline (interm. 10).

f) A dispersion of sodium hydride in mineral oil (60%) (0.021 mol) wasadded portionwise at 5° C. under N₂ flow to a mixture of intermediate(1) (0.02 mol) in DMF (30 ml). The mixture was stirred at 5° C. under N₂flow for 1 hour. A solution of intermediate (10) (0.03 mol) in a smallamount of DMF was added dropwise at 5° C. The mixture was stirred atroom temperature under N₂ flow for 2 hours, hydrolized and extractedwith EtOAc. The organic layer was separated, washed several times withH₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue(12.5 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97.5/2.5/0.1; 20–45 μm). Two pure fractions werecollected and their solvents were evaporated, yielding 7.8 g (80%) of1,1-dimethylethyl4-[[1-[(2,3-dimethyl-5-quinoxalinyl)methyl]-1H-benzimidazol-2-yl]amino]1-piperidinecarboxylate (interm. 11).

Example A4

8-Bromo-2-methylquinoline (0.0675 mol) was added portionwise at −70° C.under N₂ flow to a mixture of a solution of butyllithium in hexane(1.6M) (0.135 mol) in tetrahydrofuran (300 ml) and diethyl ether (300ml). The mixture was stirred for 30 minutes. A solution of DMF (0.405mol) in tetrahydrofuran (100 ml) was added quickly. The mixture wascooled to −70° C. and stirred for 15 minutes. Ethanol (70 ml) and aNH₄Cl solution 10% were added. The mixture was brought to roomtemperature and stirred for 15 minutes. NH₄Cl was added. The mixture wasextracted with EtOAc. The organic layer was separated, washed with H₂O,dried (MgSO₄), filtered and the solvent was evaporated. The product wasused without further purification, yielding 15 g (>100%) of2-methyl-8-quinolinecarboxaldehyde (interm. 12).

Example A5

a) A mixture of 3-methoxy-2-methylquinoline (0.081 mol) intrifluoro-acetic acid (150 ml) was hydrogenated at room temperatureunder a 34 bar pressure for 48 hours with palladium on activated carbon(2 g) as a catalyst. After uptake of hydrogen (2 equiv.), the catalystwas filtered through celite and washed with H₂O. The filtrate wasbasified with a concentrated NH₄ OH solution and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated, yielding 14.3 g (quant.) of5,6,7,8-tetrahydro-3-methoxy-2-methylquinoline (interm. 13).

b) 3-Chlorobenzenecarboperoxoic acid (0.1 mol) was added portionwise at5° C. to a mixture of intermediate (13) (0.067 mol) in dichloromethane(300 ml). The mixture was stirred at room temperature overnight,basified with K₂CO₃ 10% and separated into its layers. The aqueous layerwas extracted with CH₂Cl₂. The combined organic layer was dried (MgSO₄),filtered and the solvent was evaporated, yielding 13.7 g (quant.) of5,6,7,8-tetrahydro-3-methoxy-2-methylquinoline, 1-oxide (interm. 14).

c) A mixture of intermediate (14) (0.067 mol) in acetic anhydride (100ml) was stirred at 90° C. for 1 hour, poured out on ice and basifiedwith NaOH 3N. CH₂Cl₂ was added. The organic layer was separated, washedwith a diluted NaOH solution, dried (MgSO₄), filtered and the solventwas evaporated, yielding 16.8 g (quant.) of5,6,7,8-tetrahydro-3-methoxy-2-quinolinemethanol acetate (ester)(interm. 15). d) A mixture of intermediate (15) (0.067 mol) and sodiumhydroxide (13 g) in methanol (60 ml) was stirred and refluxed for 20minutes, poured out on ice and extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated,yielding 12.3 g (95%) of5,6,7,8-tetrahydro-3-methoxy-2-quinolinemethanol (interm. 16).

In a similar way was also prepared(O)-5,6,7,8-tetrahydro-2-methyl-8-quinolinol (interm. 17).

Example A6

Phosphorus tribromide (0.0105 mol) was added dropwise at 0° C./5° C.under N₂ flow to a mixture of(±)-5,6,7,8-tetrahydro-2-methyl-8-quinolinol (intermediate 17) (0.03mol) in toluene (20 ml). The mixture was brought to room temperature andstirred at room temperature overnight. Ice water was added. The mixturewas basified with a concentrated NaOH solution and extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (6 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1; 20–45 μm).The pure fractions were collected and the solvent was evaporated,yielding 2 g (29%) of (±)-8-bromo-5,6,7,8-tetrahydro-2-methylquinoline(interm. 18).

Example A7

a) A mixture of N-2,6-dimetyl-2,3-pyridinediamine (0.122 mol) intrifluoro-acetic acid (250 ml) was stirred and refluxed for 6 hours andbrought to room temperature. The solvent was evaporated. The residue wastaken up in CH₂Cl₂ and K₂CO₃ 10%. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (32 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc97/3; 20–45 μm). The pure fractions were collected and the solvent wasevaporated. The residue was taken up in petroleum ether. The precipitatewas filtered off and dried, yielding 15 g of residue (fraction 1). Themother layer was evaporated. The residue was combined with 14.1 g offraction 1, yielding 28.9 g of1,6-dimethyl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine; mp. 100 C(interm. 19).

b) 1-Bromo-2,5-pyrolidinedione (0.0735 mol) and dibenzoyl peroxide (1.5g) were added at room temperature to a solution of intermediate (19)(0.07 mol) in tetrachloromethane (450 ml). The mixture was stirred andrefluxed for 7 hours, then brought to room temperature and filtered. Thereaction was carried out again using the same quantities. The mixtureswere combined. The solvent was evaporated. The residue (50 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH100/0 and 98/2; 20–45 μm). The pure fractions were collected and thesolvent was evaporated, yielding 20.2 g (49%) of6-(bromomethyl)-1-methyl-2-(trifluoromethyl)1H-imidazo[4,5-b]pyridine(interm. 20).

c) A mixture of ethyl4-(1H-benzimidazol-2-ylamino)-1-piperidine-carboxylate (0.0464 mol),intermediate (20) (0.051 mol) and potassium carbonate (0.1392 mol) inacetonitrile (250 ml) was stirred and refluxed for 90 minutes and thenbrought to room temperature. Water was added and the mixture wasextracted twice with CH₂Cl₂. The combined organic layer was dried(MgSO₄), filtered and the solvent was evaporated. The product was usedwithout further purification, yielding 23 g (>100%) of ethyl4-[[1-[[1-methyl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-6-yl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 21).

Example A8

A mixture of ethyl4-(1H-benzimidazol-2-ylamino)-1-piperidine-carboxylate (0.0289 mol),7-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.0289 mol) and potassiumcarbonate (0.0867 mol) in acetonitrile (250 ml) was stirred and refluxedfor 48 hours and then brought to room temperature. The reaction wascarried out again using the same quantities. The mixtures were combined,poured out into H₂O and extracted with EtOAc. The organic layer wasseparated, washed with H₂O, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (25 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.5; 20–45 μm). Twofractions were collected and their solvents were evaporated, yielding 8g of ethyl4-[[1-(6,7-dihydro-5H-1-pyrindin-7-yl)-1H-benzimidazol-2-yl]amino])1piperidinecarboxylate (interm. 22).

Example A9

a) A dispersion of sodium hydride in mineral oil (0.261 mol) was addedportionwise at room temperature under N₂ flow to a mixture ofN-8-quinolinylformamide (0.174 mol) in DMF (500 ml). The mixture wasstirred at room temperature for 1 hour. A solution of1-chloro-2-nitrobenzene (0.53 mol) in DMF (200 ml) was added dropwise.The mixture was stirred at 140° C. for 12 hours and then brought to roomtemperature. H₂O was added and the mixture was extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue (110 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 80/20; 20–45elm). The pure fractions were collected and the solvent was evaporated,yielding 9.8 g (21%) of N-(2-nitrophenyl)-8-quinolinamine (interm. 23).

b) A mixture of 6-quinolinemethanamine (0.074 mol),2-chloro-3-nitropyridine (0.0888 mol) and potassium carbonate (0.185mol) in acetronitrile (200 ml) was stirred and refluxed for 5 hours andthen cooled to room temperature. EtOAc and H₂O were added. The mixturewas extracted with HCl 3N. The aqueous layer was basified with K₂CO₃solid and extracted with CH₂Cl₂. The combined organic layer was dried(MgSO₄), filtered and the solvent was evaporated, yielding 17.8 g (84%)of N-(3-nitro-2-pyridinyl)-8-quinolinemethanamine (interm. 24).

Example A10

a) A mixture of intermediate (24) (0.064 mol) in methanol (200 ml) washydrogenated under a 3 bar pressure for 2 hours with Raney nickel (10 g)as a catalyst. After uptake of hydrogen (3 equiv), the catalyst wasfiltered through celite and the filtrate was evaporated, yielding 14.8 g(93%) of N2-(8-quinolinylmethyl)-2,3-pyridinediamine (interm. 25).

b) A mixture of intermediate (25) (0.059 mol) and ethyl4-isothiocyanato-1-piperidinecarboxylate (0.059 mol) in methanol (150ml) was stirred and refluxed for 4 hours and brought to roomtemperature. The solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 97/3; 20–45μm). The desired fractions were collected and the solvent wasevaporated, yielding 10.5 g (37%) of ethyl4-[[[[2-[(8-quinolinylmethyl)amino]-3-pyridinyl]amino]sulfinyl]amino]-1-piperidine-carboxylate(interm. 26)

c) A mixture of intermediate (26) (0.026 mol), mercury(II) oxide (0.052mol) and sulfur (0.2 g) in ethanol (120 ml) was stirred and refluxed for2 hours, brought to room temperature and filtered over celite. Thefiltrate was evaporated, yielding 8.7 g (96%) of4-[[1-(8-quinolinylmethyl):1H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate (interm.27).

Example A11

a) A mixture of 8-quinolinecarboxaldehyde (0.092 mol) and4-methylbenzenesulfonic acid (0.3 g) in 2-ethoxyethanol (110 ml) wasstirred and refluxed for 24 hours using a Dean Stark apparatus. Thesolvent was evaporated. The reaction was carried out again using thesame quantities. The residues were combined and taken up in CH₂Cl₂. Theorganic solution was washed with K₂CO₃ 10% and decanted. The organiclayer was dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (41 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 98/2; 20–45 μm). Two pure fractions were collectedand their solvents were evaporated, yielding 20 g (34%) of8-[bis(2-ethoxyethoxy)methyl]quinoline (interm. 28).

b) A mixture of 8-quinolinecarboxaldehyde (0.248 mol), triethoxymethane(0.4464 mol) and 4-methylbenzenesulfonic acid (4 g) in ethanol (250 ml)was stirred and refluxed for 1 hour, brought to room temperature, pouredout into K₂CO₃ 10% and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theproduct was used without further purification, yielding 48.5 g (80%) of8-(diethoxymethyl)-quinoline (interm. 29).

c) A mixture of 2-quinolinecarboxaldehyde (0.08 mol) and4-methylbenzenesulfonic acid (0.25 g) in ethanol (100 ml) was stirredand refluxed for 48 hours and brought to room temperature. The reactionwas carried out again using the same quantities. The mixtures werecombined. The solvent was evaporated. The residue was taken up inCH₂Cl₂. The organic solution was washed with K₂CO₃ 10% and with H₂O,then dried (MgSO₄), filtered and the solvent was evaporated. The productwas used without further purification, yielding 32.5 g of2-(diethoxymethyl)quinoline (interm. 30).

Example A12

Intermediate (1) (0.0377 mol) and intermediate (29) (0.0755 mol) wereheated at 160° C. for 1 hour and then purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH 98/2; 15–35 μm). The purefractions were collected and the solvent was evaporated, yielding 15 g(79%) of (±)-1,1-dimethylethyl4-[[1-[ethoxy(8-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 31).

Example A13

4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at10° C. to a mixture of 1,1-dimethylethyl[1-(hydroxymethyl)-2-methylpropyl]carbamic acid (ester) (0.202 mol) inpyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H₂O (75ml) was added at 10° C. The precipitate was filtered off, washed withH₂O and taken up in CH₂Cl₂. The organic solution was washed with H₂O,dried, filtered and the solvent was evaporated, yielding 49 g (68%) of(±)-1,1-dimethylethyl[1-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2-methylpropyl]carbamate; mp.85° C. (interm. 32).

Example A14

a) A mixture of compound (33) (0.0347 mol), 1-bromo-3-methyl-2-butanone(0.052 mol) and potassium carbonate (0.104 mol) in acetonitrile (255 ml)was stirred and refluxed for 2 hours and filtered. The filtrate wasevaporated. The residue was taken up in H₂O and the mixture wasextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The product was used withoutfurther purification, yielding 16.84 g of(±)-1-[4-[[1-[ethoxy(8-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone(interm. 34) (quant.).

In a similar way were also prepared:

-   1-[4-(1H-benzimidazol-2-ylamino)-1-piperidinyl]-3-methyl-2-butanone;-   1-[4-[[1-(8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone;    and-   1-[4-[[1-(2-quinolinylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone.

b) A mixture of intermediate (34) (0.036 mol) in methanol (200 ml) wasstirred at 10° C. Sodium tetrahydroborate (0.04 mol) was added portionwise. The mixture was stirred for 90 minutes. H₂O was added. The solventwas evaporated. The residue was extracted with CH₂Cl₂. The organic layerwas separated, washed with H₂O, dried (MgSO₄), filtered and the solventwas evaporated, yielding 17 g (96%) of(±)₄-[[1[ethoxy(8-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-alpha-(1-methylethyl)-1-piperidine-ethanol(interm. 35).

c) Diethyl azodicarboxylate (0.015 mol) was added dropwise at 0° C.under N₂ flow to a solution of intermediate (35) (0.01 mol), phthalimide(0.015 mol) and triphenylphosphine (0.015 mol) in tetrahydrofuran (100ml). The mixture was stirred at room temperature for 2 hours. EtOAc wasadded. The mixture was extracted with HCl 3N and separated into itslayers. The aqueous layer was washed twice with EtOAc, basified withK₂CO₃ solid and extracted with CH₂Cl₂. The combined organic layer wasdried (MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.2; 20–45 μm). Two pure fractions werecollected and their solvents were evaporated, yielding 2.3 g (30%) of(±)-2-[2-[4-[[1-[ethoxy(8-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methylbutyl]-1H-isoindole-1,3(2H)dione(interm.

and Et₃N (0.072 mol) in CH₂Cl₂ (100 ml) was cooled to 0° C. under N₂flow. A mixture of methanesulfonyl chloride (0.036 mol) in CH₂Cl₂ (asmall amount) was added dropwise. The mixture was allowed to cool toroom temperature while stirring for 3 hours. Water was added. Themixture was decanted. The organic layer was dried (MgSO₄), filtered andthe solvent was evaporated, yielding 8.5 g of intermediate (80) (86%).

A solution of 1H-isoindole-1,3(2H)-dione (0.0828 mol) in DMF (80 ml) wascooled to 10° C. Nail 60% in oil (0.0828 mol) was added portionwise. Themixture was allowed to cool to room temperature while stir-ring for 1hour. A mixture of intermediate (80) (0.0207 mol) (prepared according toA14d) in DMF (a small amount) was added dropwise. The mixture wasstirred at room temperature for 1.5 hours, at 60° C. for 5 hours and atroom temperature for the weekend. The residue (9.6 g) was crystallizedfrom diethyl ether and CH₃CN. The precipitate was filtered off anddried, yielding 4 g of intermediate (81) (42%).

Example A15

a) A mixture of1-[4-(1H-benzimidazol-2-ylamino)-1-piperidinyl]-3-methyl-2-butanone(0.03 mol) and benzenemethanamine (0.09 mol) in methanol (200 ml) washydrogenated at 40° C. under a 3 bar pressure for 48 hours withpalladium on activated carbon (1.3 g) as a catalyst. After uptake ofhydrogen, the catalyst was filtered through celite, washed with CH₃OHand the filtrate was evaporated. Hydrogenation was continued for 24hours. After uptake of hydrogen, the catalyst was filtered throughcelite, washed with CH₃OH and the filtrate was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 85/14/1; 20–45 μm). The desired fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom diethyl ether. The precipitate was filtered off and dried, yielding0.4 g of (±)-N-[1(2-amino-3-methylbutyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 138°C. (interm. 37).

b) Di-tert-butyl dicarbonate (0.02 mol) was added at 5° C. to a mixtureof intermediate (37) (0.0186 mol) in dichloromethane (60 ma). Themixture was stirred at room temperature for 3 hours and poured out intoH₂O. The organic layer was separated, dried MgSO₄), filtered and thesolvent was evaporated. The product was used without furtherpurification, yielding 5.9 g of (±)-1,1-dimethylethyl[1-[[4-[[1-[(1,1-dimethyl-ethoxy)carbonyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]methyl]-2-methylpropyl]carbamate(interm. 38).

Example A16

A mixture of1-[4-[[1-(8-quinolinyl)-1H-benzimidazol-2-yl]amino]1-piperidinyl]-3-methyl-2-butanone(0.0222 mol) and benzenemethanamine (0.0666 mol) in methanol (250 ml)was hydrogenated at 40° C. under a 3 bar pressure for 24 hours withpalladium on activated carbon (1.5 g) as a catalyst. After uptake ofhydrogen, the catalyst was filtered through celite, washed with CH₂Cl₂and CH₃OH and the filtrate was evaporated. Palladium on activated carbon(1.5 g) and methanol (250 ml) were added again. Hydrogenation wascontinued at 40° C. under a 3 bar pressure for 24 hours. After uptake ofhydrogen, the catalyst was filtered through celite, washed with CH₂Cl₂and the filtrate was evaporated. The residue (22 g) was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH95/5/0.1 and 85/15/1; 20–45 μm). Three pure fractions were collected andtheir solvents were evaporated, yielding 2.6 g1-[4-[[1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone(interm. 40) (fraction 1), 2.9 g of fraction 2 and 0.7 g of fraction 3.Fraction 2 and 3 were crystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 0.82 g(±)-N-[1-[3-methyl-2-[(phenylmethyl)amino]butyl]4-piperidinyl]-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine;mp. 126° C. and 0.55 g ofN-(4-piperidinyl)-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine;mp. 205° C. (comp. 48).

Example A17

a) A mixture ofN-(4-piperidinyl)-1-(4-quinolinylmethyl)-1H-benzimidazol-2-amine (comp.23) (0.0129 mol), chloroacetonitrile (0.0155 mol), potassium iodide(0.00129 mol) and potassium carbonate (0.0258 mol) in4-methyl-2-pentanone (80 ml) was stirred and refluxed for 5 hours. H₂Owas added. The solvent was evaporated. H₂O and CH₂Cl₂ were added. Theprecipitate was filtered off. The filtrate was separated into itslayers. The organic layer was dried (MgSO₄), filtered and the solventwas evaporated. The residue (3.5 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/N OH 95/5/0.3; 1540em). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from CH₃CN. The precipitate was filteredoff and dried, yielding 0.94 g4-[[1-(4-quinolinylmethyl)1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile;mp. 190° C. (interm. 41).

b) A mixture of N-(4-piperidinyl)-[1,2′-bi-1H-benzimidazol]-2-amine(comp. 71) (0.01 mol), chloroacetonitrile (0.01 mol) and sodium hydrogencarbonate (0.02 mol) in DMF (50 ml) was stirred at 50° C. overnight. Thesolvent was evaporated. The residue was taken up in H₂O and the mixturewas extracted with CH₂Cl₂. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was suspended inDIPE, filtered off and dried, yielding 2.3 g (63%) of product. Thisfraction was purified over silica gel on a glass filter (eluent:CH₂Cl₂/(CH₃OH/NH₃) 97/3). The pure fractions were collected and thesolvent was evaporated, yielding 1.36 g (37%) of4-[(1,2′-bi-1H-benzimidazol-2-yl)amino]-1-piperidine-acetonitrile(interm. 42).

Example A18

A mixture of 2-chloro-1H-benzimidazole (0.0189 mol) and1,1-dimethylethyl 2-aminocyclohexanecarbamoate (0.04725 mol) (preparedaccording to A1a))was stirred at 140° C. for 3 hours, then brought toroom temperature and taken up in CH₂Cl₂/CH₃OH. The same procedure wasrepeated 3 times on the same quantities of 2-chloro-1H-benzimidazole and1,1-dimethylethyl 2-aminocyclohexanecarbamoate. The mother layers werebrought together, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (28 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.1; 15–35 μm). Twofractions were collected and the solvent was evaporated, yielding 4.5 gof intermediate (84) (24%).

Example A19

according to A14 d) and K₂CO₃ (0.0463 mol) in CH₃CN (50 ml) and DMF (5ml) was stirred and refluxed for 6 hours, poured out into H₂O andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/H₃OH 97/3; 35–70cm). The pure fractions were collected and the solvent was evaporated,yielding: 0.87 g of intermediate (76) (13%).

Example A20

A1b) in HCl 6N (60 ml) was stirred and refluxed for 12 hours and thenbrought to room temperature. The solvent was evaporated. The residue wastaken up in 2-propanol. The precipitate was filtered off, washed withCH₃CN, washed with diethyl ether and dried, yielding: 4 g ofintermediate (82) (94%).

Intermediate (82 (0.0094 mol) was added at room temperature to CH₂Cl₂(70 ml). Et₃N (0.0188 mol) was added. 1,1′-carbonylbis-1H-imidazole(0.0188 mol) was added. The mixture was stirred at room temperature for4.5 hours. (Methylamino)acetonitrile .HCl (0.0188 mol) was added. Themixture was stirred at room temperature for 12 hours. The organic layerwas separated, washed twice with water, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98.5/1.5; 35–70μm). The pure fractions were collected and the solvent was evaporated.The residue (2.2 g) was crystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding: 1.5 g of intermediate (83) (41%).

Example A21

(prepared according to Alb) in HCl 3 N (200 ml) was stirred and refluxedfor 1 hour. The solvent was evaporated. The residue was taken up inEtOAc and NH4OH. The mixture was stirred for 30 minutes and filtered.The solvent was evaporated. The product was used

Tables 1, 2 and 3 list intermediates which were prepared analogous toone of the above examples.

TABLE 1

Int. Ex. No. No. R^(a) R^(b) R^(c) n a * b R^(d) R^(e) R^(f) R^(g) 43A10c H H H 1 N 2 C — H H H 44 A12 CH₃ H O(CH₂)₂OC₂H₅ 1 CH 8 C H H H — 45A12 CH₃ H O(CH₂)₂OC₂H₅ 1 CH 2 C — H H H 46 A7c CH₃ H H 1 CH 2 N — OCH₃ —H 47 A7c H H H 1 CH 2 C — H H Cl 48 A7c H H H 1 CH 2 C — H Cl H 49 A7c HH H 1 CH 2 C — H H H 2 A1b CH₃ H H 1 CH 2 C — H H H 50 A12 CH₃ CH₃ OC₂H₅1 CH 8 C H H H — 51 A12 CH₃ H OC₂H₅ 1 CH 2 C — H H H 52 A12 CH₃ H OC₂H₅1 CH 2 C — OCH₃ H H 31 A12 CH₃ H OC₂H₅ 1 CH 8 C H H H — 53 A3f H H H 1CH 8 C H H H — 54 A3f CH₃ H H 1 CH 8 N H H — 55 A7c CH₃ H H 1 CH 8 C CH₃H H — 11 A3f CH₃ H H 1 CH 8 N CH₃ CH₃ — — 56 A7c H H H 1 CH 4 C H H — H57 A7c H CH₃ H 1 CH 8 C H H H — 27 A10c H H H 1 N 8 C H H H — 58 A10c HH — 0 CH 8 C H H H — 66 A12 CH₃ CH₃ O(C₂H₅)OC₂H₅ 1 CH 8 C H H H — 67 A12CH₃ H O(C₂H₅)OC₂H₅ 1 CH 8 C H H H — 68 A1b CH₃ CH₃ CH₃ 1 CH 8 C H H H —69 A1b CH₃ H H 1 CH 2 C — OCH₃ H H 70 A1b CH₃ H H 1 CH 2 N — H — H 71A1b CH₃ H H 1 CH 8 C OCH₃ H H — * = position bicyclic heterocycle

TABLE 2

Int. Ex. No. No. R^(a) R^(b) n L 59 A2c CH₃ H 0

60 A8 H H 0

61 A2c H H 0

5 A2c CH₃ H 0

21 A7c H H 1

62 A3f CH₃ H 1

63 A7c CH₃ H 1

64 A7c H H 1

65 A2c CH₃ H 0

22 A8 H H 0

72 A2c CH₃ CH₃ 0

73 A2c CH₃ CH₃ 0

74 A2c CH₃ CH₃ 0

75 A2c CH₃ CH₃ 0

76 A19 H H 1

TABLE 3

Int. Ex. No. No. L Physical data 77 A1b

78 A1b

79 A1b

trans 80 A14d

81 A14e

82 A20

83 A20

B. Preparation of the Final Compounds

Example B1

a) A mixture of 2-propanol and hydrochloric acid (15 ml) was added to amixture of intermediate (2) (0.0284 mol) in 2-propanol (150 ml). Themixture was stir-red and refluxed for 90 minutes and cooled. Theprecipitate was filtered off, washed with 2-propanol and DIPE and dried,yielding 10.36 g ofN-(4-piperidinyl)-1-(2-quinolinylmethyl)-1H-benzimidazol-2-aminedihydrochloride (comp. 1).

-   -   b) A mixture of compound (1) (0.01 mol) and sodium carbonate        (0.03 mol) in 4-methyl-2-pentanone (250 ml) was stirred and        refluxed for a few hours using a water separator (until gas        development stops). 2-Bromoethyl carbamic acid 1,1-dimethylethyl        ester (0.015 mol) was added. The mixture was stirred and        refluxed for 18 hours using a water separator, then cooled,        washed with H₂O, dried, filtered and the solvent was evaporated.        The residue was purified by column chromatography over silica        gel (eluent: CH₂Cl₂/C₂H₅OH 95/5 and 90/10). The pure fractions        were collected and the solvent was evaporated, yielding 3.8 g of        1,1-dimethylethyl        [2-[4-[[1-(2-quinolinylmethyl)-1H-benzimidazol-2-yl]amino]-1′-piperidinyl]ethyl]carbamate        (comp. 2).

c) A mixture of compound (2) (0.0076 mol) in a mixture of 2-propanol andhydrochloric acid (10 ml) and 2-propanol (100 ml) was stirred andrefluxed for 1 hour and then cooled. The precipitate was filtered off,washed with 2-propanol and DIPE and dried, yielding 3.08 g ofN-[1-(2-aminoethyl)₄-piperidinyl]-1-(2-quinolinylmethyl)-1H-benzimidazol-2-aminetetrahydrochloride monohydrate (comp. 3).

d) A mixture of compound (115) (0.00305 mol) in HBr/HOAc 33% (34 ml) wasstirred at room temperature for 2 hours, poured out on ice, basifiedwith a concentrated NH₄OH solution and extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2; 1540 em). Two fractions(F1 and F2) were collected and their solvents were evaporated, yielding0.56 g F1 (46%) and 0.69 g F2 (50%). F1 was crystallized from diethylether. The precipitate was filtered off and dried, yielding 0.27 g of(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine(comp. 116).

e) A mixture of compound (155) (0.0024 mol) in CH₃OH (3 ml) and2-propanol (15 ml) was stirred and refluxed for 2 hours, filtered,washed with 2-propanol and dried. The residue (1.05 g) was taken up inCH₂Cl₂ and basified with NH₄OH. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.42 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH NH₄OH 85/15/2; 15–40 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.35 g) was dissolved inCH₃OH and converted into the ethanedioic acid salt. The precipitate wasfiltered off and dried. This fraction was taken up in water and CH₂Cl₂and alkalized with K₂CO₃ 10%. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (0.21 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 75/28/1; 15–40 em). The pure fractions were collectedand the solvent was evaporated, yielding 0.13 g of compound (156).

Example B2

A mixture of intermediate (27) (0.02 mol) in hydrochloric acid (6N) (85ml) was stirred and refluxed at 50° C. overnight and then brought toroom temperature. The solvent was evaporated. The residue was taken upin K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated, yielding 5 g(69%) ofN-(4-piperidinyl)-3-(8-quinolinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine(comp. 41).

Example B3

A mixture of intermediate (41) (0.00668 mol) in a solution of ammonia inmethanol (7N) (70 ml) was hydrogenated at room temperature under a 3 barpressure for 5 hours with Raney nickel (2.7 g) as a catalyst. Afteruptake of hydrogen (2 equiv.), the catalyst was filtered through celite,washed with CH₂Cl₂ and CH₃OH and the filtrate was evaporated. Theresidue was taken up in CH₂Cl₂ and a small amount of CH₃OH. The organicsolution was washed with H₂O, dried (MgSO₄), filtered and the solventwas evaporated. The residue was crystallized from EtOAc. The precipitatewas filtered off and dried, yielding 1.6 g (60%) ofN-[1-(2-aminoethyl)₄-piperidinyl]-1-(4-quinolinylmethyl)-1H-benzimidazol-2-aminemp. 196° C. (comp. 24).

Example B4

A mixture of intermediate (36) (0.00351 mol) in hydrazine (2.5 ml) andethanol (30 ml) was stirred and refluxed for 20 minutes and brought toroom temperature. Ice water was added. The mixture was extracted withCH₂Cl₂ and separated into its layers. The aqueous layer was washed twicewith CH₂Cl₂. The combined organic layer was dried (MgSO₄), filtered andthe solvent was evaporated. The residue was taken up in diethyl ether.The precipitate was filtered off and dried, yielding 1 g of(±)-N-[1-[1-(aminomethyl)-2-methylpropyl]-4-piperidinyl]-1-[ethoxy(8-quinolinyl)methyl]-1Hbenzimidazol-2-amine; mp. 202° C. (comp. 100).

Example B5

Intermediate (32) (0.1382 mol) was added at 55° C. to a mixture of(±)-1-[ethoxy(3-methoxy-2-quinolinyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine(0.0346 mol) and potassium carbonate (0.242 mol) in acetonitrile (108ml) and DMF (20 ml) (1 equiv of intermediate (32) was added every hour).The mixture was stirred at 55° C. for 1 hour and filtered. The filtratewas poured out into H₂O and the mixture was extracted with EtOAc. Theorganic layer was separated, washed with a saturated NaCl solution,dried (MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.4 and 96/4/0.5; 20–45 μm). Two fractions werecollected and their solvents were evaporated, yielding 2.5-g (23%) of(±)-1,1-dimethylethyl[1-[[4-[[1-[ethoxy(3-methoxy-2-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]methyl]-2-methylpropyl]carbamate(comp. 38).

Example B6

A mixture of1-[4-[[1-(2-quinolinylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone(0.0158 mol) and benzenemethanamine (0.0474 mol) in methanol (150 ml)was hydrogenated at 40° C. under a 3 bar pressure for 48 hours withpalladium on activated carbon (0.7 g) as a catalyst. After uptake ofhydrogen (1 equiv), the catalyst was filtered through celite, washedwith CH₂Cl₂/CH₃OH and the filtrate was evaporated. The residue (11.5 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.5; 20–45 μm). The pure fractions werecollected and the solvent was evaporated, yielding 4 g of residue. Thisfraction was converted into the hydrochloric acid salt with2-propanol/HCl. The precipitate was filtered off and dried, yielding 5.1g of product. This fraction was converted into the free base and thenpurified by column chromatography over C₁₈ (eluent: CH₃OH/NH₄OAc 60/40and 80/20; column: KROMASIL C18). Two pure fractions were collected andtheir solvents were evaporated, yielding 0.8 g of fraction 1 and 2 g offraction 2. Fraction 1 was crystallized from diethyl ether. Theprecipitate was filtered off and dried, yielding 0.5 g of(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-quinolinylmethyl)-1H-benzimidazol-2-amine;mp. 135° C. (comp. 6). Fraction 2 was dissolved in 2-propanol andconverted into the hydrochloric acid salt (1:4). The precipitate wasfiltered off and dried, yielding 2.2 g of(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(1,2,3,4-tetrahydro-2-quinolinyl)methyl]-1H-benzimidazol-2-aminetetrahydrochloride monohydrate; mp. 230° C. (comp. 46).

Example B7

a) A dispersion of sodium hydride in a mineral oil (60%) (0.01 mol) wasadded portionwise at 0° C. under N₂ flow to a mixture of intermediate(38) (0.005 mol) in DMF (25 ml). The mixture was stirred at roomtemperature for 1 hour. A solution of 2-(bromomethyl)-3-methoxyquinoline(0.0055 mol) in DMF (10 ml) was added dropwise. The mixture was stirredat room temperature for 2 hours, hydrolized with K₂CO₃ 10% and extractedwith EtOAc. The organic layer was separated, washed with NaCl, dried(MgSO₄), filtered and the solvent was evaporated, yielding 4.5 g (>100%)of (±)-1,1-dimethylethyl[1-[[4-[[1-[(3-methoxy-2-quinolinyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinylmethyl]-2-methylpropyl]carbamate(comp. 14).

b) A dispersion of sodium hydride in a mineral oil (60%) (0.014 mol) wasadded portionwise at 0° C. under N₂ flow to a mixture of intermediate(38) (0.007 mol) in DMF (30 ml). The mixture was stirred at 5° C. for 1hour. A solution of (±)-2,8-di-bromo-5,6,7,8-tetrahydroquinoline (0.0084mol) in DMF (10 ml) was added dropwise. The mixture was stirred at roomtemperature for 2 hours. H₂O and EtOAc were added. The organic layer wasseparated, washed with a saturated NaCl solution, dried (MgSO₄),filtered and the solvent was evaporated. The residue (5.6 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.5; 20–45 μm). The pure fractions werecollected and the solvent was evaporated, yielding 1.1 g (25%) of(±)-1,1-dimethylethyl[1-[[4-[[1-(2-bromo-5,6,7,8-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]methyl]-2-methylpropyl)]-carbamate(comp. 55).

c) A mixture of intermediate 84 (0.0145 mol), 8-bromomethylquinoline(0.0174 mol) and K₂CO₃ (0.029 mol) in CH₃N (70 ml) was stirred andrefluxed for 4 hours, then brought to room temperature. The solvent wasevaporated. The residue was taken up in H₂O and extracted twice withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was crystallized from diethylether/CH₃CN. The precipitate was filtered off and dried, yielding 5.07 gof compound 79 (74%).

Example B8

c)(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(5,6,7,8-tetrahydro-3-methoxy-2-quinolinyl)methyl]-1H-benzimidazol-2-aminetetrahydrochloride monohydrate (0.0021—O— mol) was basified with K₂CO₃10%. The mixture was extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated, togive A′. A mixture of A′ in dichloromethane (50 ml) was cooled to 0° C.A solution of tribromoborane in dichloromethane (0.01526 mol) was addeddropwise. The mixture was stirred at room temperature overnight, pouredout on ice, basified with a concentrated NH₄OH solution, decanted andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.1 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 20–45 μm). The desired fractions werecollected and the solvent was evaporated. The residue was converted intothe hydrochloric acid salt salt (1:4) with HCl/2-propanol. Theprecipitate was filtered off and dried, yielding 0.5 g (37%) of(±)-N-[1-(2-amino-3-methylbutyl)₄-piperidinyl]-1-[(5,6,7,8-tetrahydro-3-hydroxy-2-quinolinyl)methyl]-1H-benzimidazol-2-aminetetrahydro-chloride monohydrate; mp. 240° C. (comp. 63).

Example B9

a) A mixture of compound 158 (0.0089 mol) in HCl 3N (40 ml) was stirredat 100° C. for 12 hours, then brought to room temperature and poured outon ice and NH₄OH. EtOAc was added. The precipitate was filtered off,washed with EtOAc and dried, yielding 2 g of compound 159.

b) A mixture of compound 168 (0.00895 mol) in HCl 3N (35 ml) was stirredat 100° C. for 24 hours. The solvent was evaporated. The residue wastaken up in EtOAc. The mixture was basified with NH₄OH. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. Part of this fraction (0.7 g) was crystallized from CH₃CN.The precipitate was filtered off and dried, yielding 0.3 g of compound167.

c) A mixture of compound 176 (0.00373 mol) in HCl 3N (20 ml) was stirredat 100° C. for 12 hours, brought to room temperature, poured out on ice,basified with NH₄OH and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Thisfraction was dissolved in 2-propanol and converted into the hydrochloricacid salt (1:3). The precipitate was filtered off and dried, yielding1.5 g of compound 173 (77%).

Example B10

(prepared according to Alb)), 1,2-ethanediamine (0.02 mol) and NaCN(0.0002 mol) in CH₃OH (7 ml) was heated at 45° C. for 4 hours and thenbrought to room temperature. Water was added. The mixture was extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue (0.65 g) was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH90/10/1; 35–70 μm). The pure fractions were collected and the solventwas evaporated, yielding 0.42 g of compound 170 (56%)

Example B 11

(prepared according to A14a)) and formic acid/NH₃ (0.0462 mol) informamide (35 ml) was stirred at 140° C. for 30 min and then brought toroom temperature. CH₂Cl₂ was added. The organic layer was separated,washed with K₂CO₃ 10%, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (4 g) was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15–40 em). Two purefractions were collected and their solvents were evaporated. The secondfraction was crystallized from CH₃CN and diethyl ether. The precipitatewas filtered off and dried, yielding: 1.37 g of compound 137 (46%).

Example B12

Isopropyl titanate (IV) (0.0294 mol) was added at room temperature to amixture of intermediate 85 (0.0245 mol) and 1-acetylpiperazine (0.027mol) in CH₂Cl₂ (50 ml) and ethanol (50 ml). The mixture was stirred atroom temperature for 7 hours. NaBH₃CN (0.0245 mol) was addedportionwise. The mixture was stirred at room temperature for 12 hours.H₂O was added. The mixture was filtered over celite and washed withCH₂Cl₂. The filtrate was separated into its layers. The organic layerwas dried (MgSO₄), filtered and the solvent was evaporated. The residue(6.7 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2; 15–40 μm). The pure fractions werecollected and the solvent was evaporated. This fraction was crystallizedfrom 2-propanone. The precipitate was filtered off and dried, yielding:0.64 g of compound 176.

Tables 4 to 13 list the compounds of formula (I) which were preparedaccording to one of the above examples.

TABLE 4

Comp Ex. No. No. a R^(a) R^(b) * R^(C) Physical data 1 B1a CH H H 2 HHCl(1:2) 2 B1b CH H H 2 ** 3 B1c CH H H 2 CH₂CH₂NH₂ HCl(1:4); H₂O(1:1) 4B1a CH H H 8 H 5 B1a CH H H 2 H 6 B5 CH H H 2 CH₂CH(2-propyl)NH₂ 7 B3 CHH H 8 CH(2-propyl)CH₂NH₂ 8 B3 CH H H 2 CH(2-propyl)CH₂NH₂ H₂O(1:1) 9 B1aCH H 8-Cl 2 H HCl(1:2) 10 B1c CH H H 8 CH₂CH(2-propyl)NH₂ 11 B3 CH H8-Cl 2 CH(2-propyl)CH₂NH₂ 12 B1a CH 4-OH H 2 H 13 B3 CH H 8-Cl 2CH₂CH(2-propyl)NH₂ 14 B6a CH 3-OCH₃ H 2 (C═O)OC(CH₃)₃ 15 B1c CH 3-OCH₃ H2 CH₂CH(2-propyl)NH₂ 16 B6a N 3-CH₃ H 2 *** 17 B1a CH H H 8 H HCl(1:3)18 B1a N H H 8 H 19 B1c N H H 8 CH₂CH(2-propyl)NH₂ HCl(1:3); H₂O(1:3) 20B1a N 3-OCH₃ H 2 H 21 B4 N 3-OCH₃ H 2 *** 22 B1c N 3-OCH₃ H 2CH₂CH(2-propyl)NH₂ 23 B1a CH H H 4 H 24 B2 CH H H 4 CH₂CH₂NH₂ 88 B1a N2-CH₃ 3-CH₃ 8 H 89 B1c N 2-CH₃ 3-CH₃ 8 CH₂CH(2-propyl)NH₂ HCl(1:4);H₂O(1:2) 90 B1a CH 2-CH₃ H 8 H 91 B1c CH 2-CH₃ H 8 CH₂CH(2-propyl)NH₂H₂O(1:1) 92 B2 CH 2-CH₃ H 8 CH₂CH₂NH₂ 104 B3 CH H H 8 CH₂CH(2-propyl)NH₂105 B3 CH H H 8 CH(2-propyl)CH₂NH₂ 106 B1c N 3-CH₃ H 2CH₂CH(2-propyl)NH₂ H₂O(1:2) 109 B5 CH H H 8 *** 110 B5 N 2-CH₃ 3-CH₃ 8*** 111 B5 CH 2-CH₃ H 8 *** 112 B5 N H H 8 *** 113 B7 CH H H 8 ****position bicyclic heterocycle **(CH₂)₂NH(C═O)OC(CH₃)₃***CH₂CH(2-propyl)NH(C═O)OC(CH₃)₃

TABLE 5

Comp Ex. Physical No. No. a R^(a) R^(b) * R^(c) G data  25 B1a CH H H 2H CHOC₂H₅  26 B3 CH H H 2 CH(2-propyl)CH₂NH₂ CHOC₂H₅ H₂O(1:1)  27 B3 CHH H 2 CH₂CH(2-propyl)NH₂ CHOC₂H₅  28 B1a CH H H 2 H ***  29 B3 CH H H 2CH(2-propyl)CH₂NH₂ *** H₂O(1:1)  30 B1a CH H H 8 H ***  31 B3 CH H H 8CH₂CH(2-propyl)NH₂ ***  32 B3 CH H H 8 CH(2-propyl)CH₂NH₂ ***  33 B1a CHH H 8 H CHOC₂H₅  34 B1a CH 3-OCH₃ H 2 H CHOC₂H₅  35 B1a N H H 2 H CH₂ 36 B4 N H H 2 ** CH₂  37 B1c N H H 2 CH₂CH(2-propyl)NH₂ CH₂ HCl(1:4) 38 B4 CH 3-OCH₃ H 2 ** CHOC₂H₅  39⁽⁹⁾ B1c CH 3-OCH₃ H 2CH₂CH(2-propyl)NH₂ CHOC₂H₅ HCl(1:3); H₂O(1:2)  40 B2 N H H 2 CH₂CH₂NH₂CH₂  41 B1a N H H 8 H CH₂  42 B1c N H H 8 CH₂CH(2-propyl)NH₂ CH₂  43 B1aCH H CH₃ 8 H CH₂  44 B1a CH H CH₃ 8 H CHOC₂H₅  45 B2 N H H 8 CH₂CH₂NH₂CH₂ 100 B3 CH H H 8 CH(2-propyl)CH₂NH₂ CHOC₂H₅ 107 B1c CH H H 8CH₂CH(2-propyl)NH₂ CHOC₂H₅ 115 B5 CH H CH₃ 8

CH₂ 116 B1d CH H CH₃ 8 CH₂CH(2-propyl)NH₂ CH₂ 117 B1d CH H CH₃ 8 CH═OCH₂ 118 B1d CH H CH₃ 8 CH₂CH₂NH₂ *** H₂O(1:1) 119 B1d CH H CH₃ 8CH₂CH(2-propyl)NH₂ *** 120 B3 N H CH₃ 8 CH₂CH₂NH₂ CH₂ HCl(1:4); H₂O(1:3)121 B1d CH H CH₃ 8 CH═O *** 122 B1c N H CH₃ 8 CH₂CH(2-propyl)NH₂ CH₂HCl(1:4); H₂O (1:1) 123 B1d CH H CH₃ 8 CH₂CH₂NH₂ CH₂ 124 B1c CH H H 8CH₂CH₂NH₂ *** HCl(1:3); H₂O(1:2) 125 B1c CH H CH₃ 8 CH₂CH₂NH₂ CHCH₃H₂O(1:1) 126 B1d CH 3-OCH₃ H 2 CH₂CH₂NH₂ CH₂ H₂O(1:2) 127 B1c CH 4-CH₃ H2 CH₂CH(2-propyl)NH₂ CH₂ HCl(1:4); H₂O(1:1) 128 B1c CH H H 8 CH₂CH₂NH₂CH₂ HCl(1:4); H₂O(1:1) 129 B1c CH H H 8 CH₂CH₂NH₂ CHCH₃ H₂O(1:1) 130 B1cCH 4-CH₃ H 2 CH₂CH₂NH₂ CH₂ HCl(1:4); H₂O(1:2) 131 B1c CH H H 4CH₂CH(2-propyl)NH₂ CH₂ HCl(1:4); H₂O(1:2) 131 B1b CH H CH₃ 8

CH₂ 132 B1b CH H H 8

CH₂ 133 B2 CH H H 8 H CHCH₃ HCl(1:2); H₂O(1:2) 134 B1c CH H H 2CH₂CH₂NH₂ CHCH₃ H₂O(1:1) 135 B2 CH 4-CH₃ H 2 H CH₂ HCl(1:2) 136 B2 N HCH₃ 8 H CH₂ 137 B11 CH H H 8 CH═O CH₂ *position quinoline**CH₂CH(2-propyl)NH(C═O)OC(CH₃)₃ ***CHO(CH₂)₂OC₂H₅

TABLE 6

Comp. Ex. No. No. * G R^(a) Physical data 46 B5 2 CH₂ CH₂CH(2-propyl)NH₂HCl(1:4); H₂O(1:1) 47 B5 8 CH₂ CH₂CH(2-propyl)NH₂ HCl(1:4); H₂O(1:1) 48B5 8 — H 49 B5 8 — CH₂CH(2-propyl)NH₂ H₂O(1:1) *position bicyclicheterocycle

TABLE 7

Co. Ex. No. No. * a R^(a) G R^(b) R^(c) Physical data  50 B1a 8 CH H — HH  51 B5 8 CH H — CH₂CH(2-propyl)NH₂ H  52 B1a 8 N H — H H HCl(1:3)  53B3 8 N H — CH(2-propyl)CH₂NH₂ H  54⁽³⁾ B3 8 N H — CH₂CH(2-propyl)NH₂ HH₂O(1:1)  55 B6b 8 CH 2-Br — ** H  56 B1c 8 CH 2-Br — CH₂CH(2-propyl)NH₂H HCl(1:3); H₂O(1:3)  57 B6b 8 CH 2-CH₃ — ** H  58 B1c 8 CH 2-CH₃ —CH₂CH(2-propyl)NH₂ H HCl(1:4); H₂O(1:1)  59 B6a 2 CH H CH₂ ** H  60 B1c2 CH H CH₂ CH₂CH(2-propyl)NH₂ H HCl(1:4); H₂O(1:1)  61 B6a 2 CH 3-OCHCH₂ ** H  62 B1c 2 CH 3-OCH CH₂ CH₂CH(2-propyl)NH₂ H HCl(1:4); H₂O(1:1) 63 B7 2 CH 3-OH CH₂ CH₂CH(2-propyl)NH₂ H HCl(1:4); H₂O(1:1)  64 B1a 8 N3-Cl — H H  65 B4 8 N 3-Cl — ** H  66 B1c 8 N 3-Cl — CH₂CH(2-propyl)NH₂H HCl(1:3); H₂O(1:1)  67 B2 8 N H — CH₂CH₂NH₂ H HCl(1:3); H₂O(1:3)  68B1a 8 N 2-Cl — H H  69 B4 8 N 2-Cl — ** H  70⁽¹⁰⁾ B1c 8 N 2-Cl —CH₂CH(2-propyl)NH₂ H HCl(1:3); H₂O(1:1) 139 B1c 5 N 3-Cl — CH₂CH₂NH₂ CH₃HCl(1:3); H₂O(1:2) 140 B1d 5 N H — CH₂CH(2-propyl)NH₂ CH₃ 141 B1c 5 N2-Cl — CH₂CH₂NH₂ CH₃ HCl(1:3); H₂O(1:3) 142 B1c 5 N 2-Cl —CH₂CH(2-propyl)NH₂ CH₃ *position bicyclic heterocycle**CH₂CH(2-propyl)NH(C═O)OC(CH₃)₃

TABLE 8

Comp. Ex. No No. a b R^(a) R^(b) G R^(c) Physical data 71 N N H H — H 72S N — H — H HBr (1:2); H₂O (2:1) 73 B1a O N — H — H 74 N N H H CH₂ H 75N N H H CH₂ CH₂CH₂NH₂ H₂O(1:1) 76 O CH — H CH₂ H 77 N N CH₃ H CH₂ H 78B1c N N CH₃ H CH₂ CH₂CH₂NH₂ 79 S CH — H CH₂ H 80 B1a S N — H CH₂ HHCl(1:2); H₂O(1:1) 81 B2 N N H H — CH₂CH₂NH₂ HCl(1:4) 82 B1a N N H OCH₃CH₂ H 83 B1b S N — H — * H₂O(1:1) 84 B1c S N — H — CH₂CH₂NH₂ HCl(1:3);H₂O(1:1) 85 B1b N N CH₃ H CH₂ * 86 B1b O N — H — * 87 B1c O N — H —CH₂CH₂NH₂ *CH₂CH₂NH(C═O)OC(CH₃)₃

TABLE 9

Comp. No. Ex. No. R^(a) Physical data 102 B1a H HCl(1:3) 103 B5CH₂CH(2-propyl)NH₂ H₂O(1:1)

TABLE 10

Rnr Comp. Ex. No. No. R^(b) R^(c) G—R^(a) Physical data 93 H H

101 CH₂CH₂NH₂ H

94 CH₂CH₂NH(C═O)OCH₂CH₃ H

95 CH₂CH₂NH₂ H

96 B1a H H

97 B2 CH₂CH₂NH₂ H

HCl(1:3); H₂O(1:1) 98 B1a H H

99 B1c CH₂CH(2-propyl)NH₂ H

HCl(1:3); H₂O(1:3) 108 B5 CH₂CH(2-propyl)NH₂ H

114 * H

143 B6 CH₂CH(2-propyl)NH₂ CH₃

*CH₂CH(2-propyl)NH(C═O)OC(CH₃)₃

TABLE 11

Co Ex. Physical No. No. a—a1—a2—a3 * R^(a) R^(c) R^(b) G data 144 B1cCH═N—CH═C 8 H — CH₂CH(2-propyl)NH₂ CH₂ HCl(1:3); H₂O(1:4) 145 B1cCH═C—N═C 8 H H CH₂CH(2-propyl)NH₂ CH₂ HCl(1:3); H₂O(1:2) 146 B1cCH═C—C═N 8 — H CH₂CH(2-propyl)NH₂ CH₂ HCl(1:3); H₂O(1:2) 147 B2CH═C—CH═C 8 CH₃ Cl H CH₂ 148 B3 CH═N—CH═C 8 H — CH₂CH₂NH₂ CHOC₂H₅ 149 B2CH═C—CH═N 8 — H H CH₂ HCl(1:2); H₂O(1:1) 150 B1c CH═C—CH═C 7 CH₃ ClCH₂CH₂NH₂ CH₂ HCl(1:4); H₂O(1:2) 151 B3 CH═N—CH═C 8 H — CH₂CH₂NH₂ CH₂152 B2 CH═N—CH═C 8 H — H CH₂ HCl(1:4); H₂O(1:2) 153 B3 CH═C—CH═N 8 — HCH₂CH₂NH₂ CHOC₂H₅ *position bicyclic heterocycle

TABLE 12

Co Ex. Physical No. No. R^(a) R^(b) data 154 B1c H 3-propylamineHCl(1:3); H₂O(1:1) 155 B1b H

156 B1e H

157 B7c H

trans 158 B7c H

159 B9a H 2-ethylamine 160 B1c H 3-propylmethylamine 161 B1c H

cis; HCl(1:3); H₂O(1:1) 162 B1c H

HCl(1:4); H₂O(1:1) 163 B4 H 3-isobutylamine 164 B1c H 2-ethylmethylamineHCl(1:2) 165 B1a H

trans; H₂O(1:1) 166 B9a CH₃ 2-ethylamine 167 B9b H

cis 168 B7c H

cis 169 B3 H

HCl(1:3); H₂O(1:2) 170 B10 H

171 B10 H

H₂O(1:1) 172 B1c H

HCl(1:4); H₂O(1:2) 173 B9c H

HCl(1:3) H₂O(1:2) 174 B1c H

175 B7c H

cis 176 B12 H

TABLE 13

Co Ex. Physical No. No. G L a. R_(a). data 177 B1d 2-ethylamine

CH H HCl(1:3); H₂O(1:3) 178 B1c 2-ethylamine

N H HCl(1:4); H₂O(1:4) 179 B1c 2-ethylamine

CH CH3 H₂O(1:1) 180 B1b

CH H 181 B1c

CH H HCl(1:3); H₂O(1:2) 182 B1c 2-ethylamine

CH H HCl(1:3); H₂O(1:2) 183 B1c 2-ethylamine

CH H 184 B1c 2-ethylamine

CH H HCl(1:4); H₂O(1:1) 185 B1d 2-ethylamine

CH H C₂H₂O₄(2:7)

TABLE 14 Physical data Comp. C H N melting No. Theor. Exp. Theor. Exp.Theor. Exp. point 1 61.40 60.70 5.85 6.04 16.27 15.54 3 51.08 51.16 6.076.35 14.89 14.17 4 73.92 73.29 6.49 6.52 19.59 19.38 206° C. 6 73.2773.12 7.74 7.73 18.99 18.77 135° C. 7 73.27 71.85 7.74 7.80 18.99 18.61188° C. 8 70.40 69.73 7.88 7.40 18.24 17.56  80° C. 9 >250° C.   1073.27 72.82 7.74 7.58 18.99 18.63 172° C. 11 190° C. 13 67.98 66.43 6.976.79 17.62 17.02 164° C. 15 71.16 70.66 7.68 7.58 17.78 17.81 210° C. 1951.45 51.64 6.97 6.89 16.15 15.96 240° C. 22 68.47 68.04 7.45 7.52 20.7020.55 206° C. 23 73.92 71.70 6.49 6.53 19.59 19.92 140° C. 24 71.9769.89 7.05 7.10 20.98 20.07 196° C. 89 51.46 53.22 6.94 7.11 15.00 15.14 24° C. 91 70.85 69.82 8.07 8.29 17.71 17.48 180° C. 92 72.43 71.51 7.297.30 20.27 20.10 176° C. 104 72.87 70.26 7.53 7.27 19.61 18.73  88° C.105 72.87 71.37 7.53 7.39 19.61 19.39 135° C. 106 65.69 66.19 7.96 7.6219.86 19.71 110° C. 26 69.02 69.16 7.99 7.68 16.65 16.79 140° C. 2771.57 70.60 7.87 7.80 17.27 17.14 166° C. 29 67.86 67.64 8.08 7.79 15.3215.15 100° C. 31 70.16 68.97 7.98 7.97 15.84 15.56 110° C. 32 70.1669.35 7.98 8.34 15.84 14.73  98° C. 33 71.79 70.72 6.78 7.17 17.44 16.69145° C. 37 215° C. 39 209° C. 40 68.80 66.01 6.78 6.60 24.42 23.31 138°C. 42 70.40 69.14 7.50 7.50 22.10 21.68 180° C. 43 74.36 73.02 6.78 6.6518.85 18.41 155° C. 44 72.26 71.53 7.03 7.26 16.85 16.40 186° C. 4568.80 66.74 6.78 6.64 24.42 23.77 178° C. 100 71.57 71.16 7.87 7.9317.27 17.44 202° C. 107 71.57 69.77 7.87 7.85 17.27 16.40  78° C. 46230° C. 47 230° C. 48 72.59 71.54 7.25 7.13 20.16 19.91 205° C. 49 69.3070.08 8.50 8.37 18.65 18.93 140° C. 51 72.19 70.66 8.39 8.43 19.43 18.79120° C. 53 69.25 68.88 8.14 8.28 22.61 22.23 54 66.49 66.30 8.26 7.7721.71 21.53 144° C. 56 46.27 47.19 6.57 6.44 12.45 12.16 >250° C.   58210° C. 60 212° C. 62 52.51 53.38 7.24 7.63 13.12 12.37 240° C. 63 51.7652.74 7.08 7.32 13.41 12.93 240° C. 66 50.43 50.60 6.60 6.58 16.4716.28 >250° C.   67 47.62 46.73 6.90 6.83 17.67 17.19 230° C. 70 238° C.80 210° C. 81 48.38 47.77 5.61 5.61 82 67.00 66.51 6.43 6.29 22.32 22.1283 61.15 62.11 6.71 6.60 16.46 16.88 84 48.51 48.46 5.62 5.35 16.1616.03 87 67.00 66.42 6.43 6.55 22.32 21.80 103 68.78 68.77 8.31 8.2319.25 18.78  88° C. 96 58.73 58.59 5.16 5.03 22.83 22.40 144° C. 97 210°C. 99 53.51 52.63 7.15 7.02 13.87 13.24 200° C. 108 70.08 68.99 7.928.10 22.00 21.65 160° C. 116 203° C. 117 218° C. 141 225° C. 177 >260°C.   139 190° C. 118  48° C. 144 220° C. 143 70.55 66.03 8.11 8.14 21.3318.98 119 145° C. 121 185° C. 140 172° C. 120 210° C. 142  98° C. 122245° C. 154  90° C. 145 190° C. 123 194° C. 124 150° C. 146 240° C. 125 74° C. 178 160° C. 150 >250° C.   126  90° C. 127 200° C. 128 210° C.157 185° C. 159 140° C. 151 212° C. 160 73.02 72.95 6.71 6.70 20.2720.35 129 170° C. 130 150° C. 131 >250° C.   152 230° C. 153 169° C. 131120° C. 161 206° C. 132 160° C. 133 210° C. 134  81° C. 162 210° C.147 >250° C.   163 168° C. 179 116° C. 135 62.16 62.10 6.12 6.06 15.7615.71 164 146° C. 136 188° C. 165 112° C. 166 114° C. 149 210° C. 180247° C. 167 167° C. 181 235° C. 182 >250° C.   184 47.75 47.58 6.01 6.3717.72 17.00 169 180° C. 170  73° C. 171  72° C. 172 178° C. 173 190° C.137 196° C. 175 228° C. 176 168° C. 185 158° C.

C. Pharmacological Example Example C1 In vitro Screening for ActivityAgainst Respiratory Syncytial Virus.

The percent protection against cytopathology caused by viruses(antiviral activity-or IC₅₀) achieved by tested compounds and theircytotoxicity (CC₅₀) were both calculated from dose-response curves. Theselectivity of the anti viral effect is represented by the selectivityindex (SI), calculated by dividing the CC₅₀ (cytotoxic dose for 50% ofthe cells) by the IC₅₀ (antiviral activity for 50% of the cells).

Automated tetrazolium-based colorimetric assays were used fordetermination of IC₅₀ and CC₅₀ of test compounds. Flat-bottom, 96-wellplastic microtiter trays were filled with 180 μl of Eagle's BasalMedium, supplemented with 5% FCS (0% for FLU) and 20 mM Hepes buffer.Subsequently, stock solutions (7.8×final test concentration) ofcompounds were added in 45 μl volumes to a series of triplicate wells soas to allow simultaneous evaluation of their effects on virus- andmock-infected cells. Five fivefold dilutions were made directly in themicrotiter trays using a robot system. Untreated virus controls, andHeLa cell controls were included in each test. Approximately 100 TCID₅₀of Respiratory Syncytial Virus was added to two of the three rows in avolume of 50 μl. The same volume of medium was added to the third row tomeasure the cytotoxicity of the compounds at the same concentrations asthose used to measure the antiviral activity. After two hours ofincubation, a suspension (4×10⁵ cells/ml) of HeLa cells was added to allwells in a volume of 50 μl. The cultures were incubated at 37° C. in a5% CO₂ atmosphere. Seven days after infection the cytotoxicity and theantiviral activity was examined spectrophotometrically. To each well ofthe microtiter tray, 25 μl of a solution of MT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) wasadded. The trays were further incubated at 37° C. for 2 hours, afterwhich the medium was removed from each cup. Solubilization of theformazan crystals was achieved by adding 100 μl 2-propanol. Completedissolution of the formazan crystals were obtained after the trays havebeen placed on a plate shaker for 10 min. Finally, the absorbances wereread in an eight-channel computer-controlled photometer (Multiskan MCC,Flow Laboratories) at two wavelengths (540 and 690 nm). The absorbancemeasured at 690 nm was automatically subtracted from the absorbance at540 nm, so as to eliminate the effects of non-specific absorption.Particular IC₅₀, CC₅₀ and SI values are listed in Table 15 hereinbelow.

TABLE 15 Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 42 0.0004 >10.05 >25119 310.0008 12.68 15849 56 0.0016 12.71 7943 145 0.00631 25.12 3981 6 0.012610.00 794 156 0.01259 19.95 1585 131 0.0316 19.94 631 530.1259 >9.95 >79 29 0.3162 10.12 32 148 1 25 25 97 1.5849 >99.85 >63

1. A compound of formula

an N-oxide, addition salt, quaternary amine, metal complex orstereochemically isomeric form thereof wherein -a¹=a²-a³=a⁴- representsa bivalent radical of formula —CH═CH—CH═CH— (a-1); wherein each hydrogenatom in the radical (a-1) may optionally be replaced by halo, CH₆alkyl,nitro, amino, hydroxy, CH₆alkyloxy, polyhaloC₁₋₆alkyl, carboxyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl, or a radical of formula

wherein ═Z is ═O, ═CH—C(═O)_NR^(5a) R^(5b), ═CH₂, ═CH—C₁₋₆alkyl, ═N—OHor ═N—O—C₁₋₆ alkyl; Q is a radical of formula

wherein Alk is C₁₋₆alkanediyl; Y¹ is a bivalent radical of formula—NR²_or —CH(NR²R⁴)—; X¹ is NR⁴, S, S(═O), S(═O)₂, O, CH₂, C(═O),C(═CH₂), CH(OH), CH(CH₃), CH(OCH₃), CH(SCH₃), CH(NR_(5a)R_(5b)), CH₂—NR⁴or NR⁴—CH₂; X² is a direct bond, CH₂, C(═O), NR⁴, C₁₋₄alkylene-NR⁴, orNR⁴—C₁₋₄alkylene; t is 2, 3, 4 or 5; u is 1,2,3, 4 or 5; v is 2 or 3;and whereby each hydrogen atom in Alk and the carbocycles and theheterocycles defined in radicals (b-3), (b-4), (b-5), (b-6), (b-7) and(b-8) may optionally be replaced by R³; with the proviso that when R³ ishydroxy or C₁₋₆alkyloxy, then R³ can not replace a hydrogen atom in theα position relative to a nitrogen atom; G is a direct bond orC₁₋₁₀alkanediyl optionally substituted with one, two or threesubstituents selected from hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy,C₁₋₆alkylthio, arylC₁₋₆alkylthio, arylcarbonyl, HO(—CH₂—CH₂—O)_(n)—,C₁₋₆alkyloxy(—CH₂CH₂—O)_(n)—, arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, amino,mono-or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino and aryl; R¹ is abicyclic heterocycle selected from quinolinyl, quinoxalinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,pyridopyridyl, naphthyridinyl, 1H-imidazo[4,5-b]pyridinyl,3H-imidazo[4,5b]pyridinyl, imidazo[1,2-a]pyridinyl,2,3-dihydro-1,4-dioxino[2,3-b]pyridyl or a radical of formula

and said bicyclic heterocycles may optionally be substituted in eitherof the two cycles with 1 or where possible more substituents selectedfrom halo, hydroxy, amino, cyano, carboxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, mono-or di(C₁₋₆alkyl)amino, mono-ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkylcarbonylamino,C₁₋₆alkyl-SO₂—NR^(5c)—, aryl-SO₂—NR^(5c)—, C₁₋₆alkyloxycarbonyl,—C(═O)—NR^(5c)R^(5d), HO(—CH₂-CH₂—O)_(n)—, halo(—CH₂—CH₂—O)_(n)—,C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, arylC₁₋₆alkyloxy(—CH₂CH₂—O)_(n)— andmono-or di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—; each n independently is 1,2, 3 or 4; each m independently is 1 or 2; each p independently is 1 or2; each R² independently is hydrogen, formyl, C₁₋₆alkylcarbonyl,Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C₃₋₇cycloalkylsubstituted with N(R⁶)₂, or C₁₋₁₀alkyl substituted with N(R⁶)₂ andoptionally with a second, third or fourth substituent selected fromamino, hydroxy, C₃₋₇cycloalkyl, C₂₋₅alkanediyl (wherein saidC₂₋₅alkanediyl is substituted on one carbon atom of said C₁₋₁₀ alkylsubstituted with N(R ⁶)₂ to form a spiro moiety), piperidinyl, mono-ordi(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, aryl and aryloxy; R³ ishydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, arylC₁₋₆alkyl orarylC₁₋₆alkyloxy; R⁴ is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl; R^(5a),R^(5b), R^(5c) and R^(5d) each independently are hydrogen or CH₆alkyl;or R^(5a) and R^(5b), or R^(5c) and R^(5d) taken together form abivalent radical of formula —(CH₂)_(n)— wherein s is 4 or 5; R⁶ ishydrogen, CH₄alkyl, formyl, hydroxyC₁₋₆alkyl, CH₆alkylcarbonyl orC₁₋₆alkyloxycarbonyl; aryl is phenyl or phenyl substituted with 1 ormore substituents selected from halo, hydroxy, CH₆alkyl,hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, and CH₆alkyloxy; and Het ispyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
 2. A compound accordingto claim 1, wherein Q is a radical of formula (b-5) wherein v is 2 andY¹ is —NR²—.
 3. A compound according to claim 1, wherein R² isC₁₋₁₀alkyl substituted with NHR⁶.
 4. A compound according to claim 1,wherein G is a direct bond or C₁₋₁₀alkanediyl optionally substitutedwith one, two or three substituents selected from the group consistingof hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, HO(—CH₂—CH₂—O)_(n)—,C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, and arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—. 5.A compound wherein the compound is(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-4-methyl-1-[1-(8-quinolinyl)ethyl]-1H-benzimidazol-2-aminemonohydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-bromo-5,6,7,8-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-aminetrihydrochloride trihydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-4-methyl-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-aminetrihydrochloride trihydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(ethoxy-8-quinolinylmethyl)-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine;N-[1-(2-aminoethyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;N-[1-(8-quinolinylmethyl)-1H-benzimidazol-2-yl]-1,3-propanediaminetrihydrochloride monohydrate;(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-aminetrihydrochloride dihydrate;(±)-N-[1-[1-(aminomethyl)-2-methylpropyl]-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(1-isoquinolinylmethyl)1H-benzimidazol-2-aminetrihydrochloride trihydrate;N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-aminetrihydrochloride trihydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-aminetrihydrochloride trihydrate;(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-2,3-dimethyl-5-quinoxalinyl)-1H-benzimidazol-2-aminetrihydrochloride trihydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloridemonohydrate;(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-aminetrihydrochloride dihydrate;(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-4-methyl-1H-benzimidazol-2-aminemonohydrate;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine;((1-isoquinolin-1-ylmethyl)-1H-benzoimidazol-2-yl)-piperidin-4-yl-amine;(1-(4-(1-isoquinolin-1-ylmethyl-1H-benzoimidazol-2-ylamino)-piperidin-1-ylmethyl)-2-methyl-propyl)-carbamicacid tert-butyl ester; or an N-oxide, addition salt, quaternary amine,metal complex or stereochemically isomeric form thereof.
 6. A method oftreating a respiratory syncytial viral infection, comprising the step ofadministering a therapeutically effective amount of a compound asclaimed in any one of claims 1 and 3 to
 6. 7. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound asclaimed in any one of claims 1 and 2 to
 5. 8. A process of preparing acomposition as claimed in claim 7, comprising the step of intimatelymixing said carrier with said compound.
 9. An intermediate of formula

with R¹, G and -a¹=a²-a³=a⁴- defined as in claim 1, P being a protectivegroup, and Q1 being defined as Q according to claim 1 but being devoidedof the R² or R⁶ substituent.
 10. An intermediate of formula

with R¹, G and -a¹=a²-a³=a⁴- defined as in claim 1, and (O═)Q₃ being acarbonyl derivative of Q, said Q being defined according to claim 1,provided that it is devoided of the NR²R⁴ or NR² substituent.
 11. Anintermediate of formula

with R¹, Q and -a¹=a²-a³=a⁴- defined as in claim 1, and (O═)G₂ being acarbonyl derivative of G, said G being defined according to claim
 1. 12.A process of preparing a compound as claimed in claim 1, comprising atleast one step selected from the group consisting of: a) reacting anintermediate of formula (II-a) or (II-b) with an intermediate of formula(III)

 with R¹, G, Q and -a¹=a²-a³=a⁴- defined as in claim 1, and W₁ being asuitable leaving group, in the presence of a suitable base and in asuitable reaction-inert solvent; b) deprotecting an intermediate offormula (IV)

 with R¹, G, and -a¹=a 2-a³=a⁴- defined as in claim 1, H-Q, beingdefined as Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, and P being a protective group; c) deprotectingand reducing an intermediate of formula (IV-a)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, H-Q₁ being definedas Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, Q_(1a)(CH═CH) being defined as Q₁ provided thatQ₁ comprises an unsaturated bond, and P being a protective group; d)deprotecting an intermediate of formula (V)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₂ beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen; e) deprotecting an intermediateof formula (VI)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₂ beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen, and P being a protective group;f) deprotecting an intermediate of formula (VII) or (VIII)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, H-Q_(1′)(OH) beingdefined as Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen and provided that Q comprises a hydroxy moiety,H₂N-Q_(2′)(OH) being defined as Q according to claim 1 provided thatboth R⁶ substituents are hydrogen or R² and R⁴ are both hydrogen andprovided that Q comprises a hydroxy moiety, and P being a protectivegroup; g) amination of an intermediate of formula (IX)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₃H beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen, and the carbon adjacent to thenitrogen carrying the R⁶, or R² and R⁴ substituents contains at leastone hydrogen, in the presence of a suitable amination reagent; h)reducing an intermediate of formula (X)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N—CH₂—Q₄being defined as Q according to claim 1 provided that Q comprises a—CH₂—NH₂ moiety, in the presence of a suitable reducing agent; i)reducing an intermediate of formula (X-a)

 with G, and -a¹=a²-a³=a⁴- defined as in claim 1, H₂N—CH₂—Q₄ beingdefined as Q according to claim 1 provided that Q comprises a —CH₂—NH₂moiety, and R^(1′) being defined as R¹ according to claim 1 providedthat it comprises at least one substituent, in the presence of asuitable reducing agent and suitable solvent; j) amination of anintermediate of formula (XI)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, andH₂N—CH₂—CHOH—CH₂—Q₄ being defined as Q according to claim 1 providedthat Q comprises a CH₂—CHOH—CH₂—NH₂ moiety, in the presence of asuitable amination reagent; k) reacting an intermediate of formula (XII)with formic acid, formamide and ammonia

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H—C(═O)-Q₁being defined as Q according to claim 1 provided that R² or at least oneR⁶ substituent is formyl; l) amination of an intermediate of formula(XIII) by reaction with an intermediate of formula (XIV)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and R^(2a)—NH-HQ₅being defined as Q according to claim 1 provided that R² is other thanhydrogen and is represented by R^(2a), R⁴ is hydrogen, and the carbonatom adjacent to the nitrogen atom carrying the R² and R⁴ substituents,carries also at least one hydrogen atom, in the presence of a suitablereducing agent; m) reducing an intermediate of formula (XV)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and(R⁶)₂N-[(C₁₋₉alkyl)CH₂OH]—NH-HQ₅ being defined as Q according to claim 1provided that R² is other than hydrogen and is represented by C₁₋₁₀alkylsubstituted with N(R⁶)₂ and with hydroxy, and the carbon atom carryingthe hydroxy, carries also two hydrogen atoms, and provided that R⁴ ishydrogen, and the carbon atom adjacent to the nitrogen atom carrying theR² and R⁴ substituents, carries also at least one hydrogen atom, with asuitable reducing agent; n) deprotecting an intermediate of formula(XVI), (XVI-a) or (XVI-b)

 with G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H-Q, being definedas Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, and R^(1a)(A—O—H)_(w), R^(1a′)-(A—O—H)₂ andR^(1a′)-(A—O—H)₃ being defined as R¹ according to claim 1 provided thatR¹ is substituted with hydroxy, hydroxyC₁₋₆alkyl, orHO(—CH₂—CH₂—O)_(n)—, with w being an integer from 1 to 4 and P or P₁being a suitable protecting group, with a suitable acid; o) amination ofan intermediate of formula (XVII)

 with R¹, G, -a¹=a²-a 3=a⁴-, Alk, X¹ R² and R⁴ defined as in claim 1, inthe presence of a suitable amination agent; p) amination of anintermediate of formula (XIX)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, andQ₆N—CH₂—C₁₋₃alkyl-NR⁴ being defined as Q according to claim 1 providedthat in the definition of Q, X² is C₂₋₄alkyl-NR⁴, in the presence of asuitable amination agent; q) deprotecting an intermediate of formula(XXI)

with R¹, Q, and -a¹=a²-a³=a⁴- defined as in claim 1, and HO-G1 beingdefined as G according to claim 1 provided that G is substituted withhydroxy or HO(CH₂CH₂O—)_(n); and r) reducing an intermediate of formula(XXII)

with R¹, Q, and -a¹=a 2-a³=a⁴- defined as in claim 1, and H-G₂-OH beingdefined as G according to claim 1 provided that G is substituted withhydroxy and the carbon atom carrying the hydroxy substituent carriesalso at least one hydrogen, in the presence of a suitable reducingagent.
 13. The process of claim 12, further comprising the step ofconverting compound of formula (I′), stereochemically isomeric forms,metal complexes, quaternary amines or N-oxide forms thereof, into atherapeutically active non-toxic acid addition salt by treatment with anacid.
 14. The process of claim 12, further comprising the step ofconverting compound of formula (I′), stereochemically isomeric forms,metal complexes, quaternary amines or N-oxide forms thereof, into atherapeutically active non-toxic base addition salt by treatment withalkali.
 15. The process of claim 12, further comprising the step ofconverting the acid addition salt form of compound of formula (I′),stereochemically isomeric forms, metal complexes, quaternary amines orN-oxide forms thereof, into the free base by treatment with alkali. 16.The process of claim 12, further comprising the step of converting thebase addition salt form of compound of formula (I), stereochemicallyisomeric forms, metal complexes, quaternary amines or N-oxide formsthereof, into the free acid by treatment with acid.